Frank Lehmann-Horn1, Adele D'Amico2, Enrico Bertini2, Mauro Lomonaco3, Luciano Merlini4, Kevin R Nelson5, Heike Philippi6, Gabriele Siciliano7, Frank Spaans8, Karin Jurkat-Rott9. 1. Division of Neurophysiology, Ulm University, Ulm, Germany. 2. Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Bambino Gesù Children's Hospital, Rome, Italy. 3. Department of Neurosciences, Catholic University, Rome, Italy. 4. Laboratory of Musculoskeletal Cell Biology, Instituto Ortopedico Rizzoli, Bologna, Italy. 5. Medical Affairs, University of Kentucky, Lexington, KY, USA. 6. Frankfurt University, Sozialpädiatrisches Zentrum, Epilepsieambulanz, Frankfurt, Germany. 7. Department of Clinical and Experimental Medicine, Neurological Unit, University of Pisa, Italy. 8. Clinical Neurophysiology, Maastricht University, Maastricht, The Netherlands. 9. Department of Neurosurgery, Ulm University, Ulm, Germany.
Abstract
INTRODUCTION: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. METHODS: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. RESULTS: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. DISCUSSION: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.
INTRODUCTION: Myotonia permanens due to Nav1.4-G1306E is a rare sodium channelopathy with potentially life-threatening respiratory complications. Our goal was to study phenotypic variability throughout life. METHODS: Clinical neurophysiology and genetic analysis were performed. Using existing functional expression data we determined the sodium window by integration. RESULTS: In 10 unrelated patients who were believed to have epilepsy, respiratory disease or Schwartz-Jampel syndrome, we made the same prima facie diagnosis and detected the same heterologous Nav1.4-G1306E channel mutation as for our first myotonia permanens patient published in 1993. Eight mutations were de-novo, two were inherited from the affected parent each. Seven patients improved with age, one had a benign phenotype from birth, and two died of respiratory complications. The clinical features age-dependently varied with severe neonatal episodic laryngospasm in childhood and myotonia throughout life. Weakness of varying degrees was present. The responses to cold, exercise and warm-up were different for lower than for upper extremities. Spontaneous membrane depolarization increased frequency and decreased size of action potentials; self-generated repolarization did the opposite. The overlapping of steady-state activation and inactivation curves generated a 3.1-fold window area for G1306E vs. normal channels. DISCUSSION: Residue G1306 Neonatal laryngospasm and unusual distribution of myotonia, muscle hypertrophy, and weakness encourage direct search for the G1306E mutation, a hotspot for de-novo mutations. Successful therapy with the sodium channel blocker flecainide is due to stabilization of the inactivated state and special effectiveness for enlarged window currents. Our G1306E collection is the first genetically clarified case series from newborn period to adulthood and therefore helpful for counselling.
Entities:
Keywords:
muscular and respiratory tract diseases; neonate; stridor
Authors: Jean-François Desaphy; Annamaria De Luca; Maria Paola Didonna; Alfred L George; Diana Camerino Conte; Annamaria D E Luca Journal: J Physiol Date: 2003-11-07 Impact factor: 5.182
Authors: Rahul R Singh; S Veronica Tan; Michael G Hanna; Stephanie A Robb; Antonia Clarke; Heinz Jungbluth Journal: Pediatrics Date: 2014-10-13 Impact factor: 7.124
Authors: Dilşad Türkdoğan; Emma Matthews; Sunay Usluer; Aslı Gündoğdu; Kayıhan Uluç; Roope Mannikko; Michael G Hanna; Sanjay M Sisodiya; Hande S Çağlayan Journal: Epilepsia Open Date: 2019-07-01