Mutations in the Sodium Channel Gene SCN2A Cause Neonatal Epilepsy with Late-Onset Episodic
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Mutations in the sodium channel gene SCN2A cause neonatal epilepsy with late-onset episodic ataxia
N. Schwarz, MD1, A. Hahn, MD2, T. Bast, MD3, S. Müller, Dipl. Biol.1, H. Löffler1, S. Maljevic, PhD1, E. Gaily, MD, PhD4, I. Prehl, Dipl. Biol.5, S. Biskup, MD, PhD5, 6, T. Joensuu, PhD7, A.-E. Lehesjoki, MD, PhD7, B. A. Neubauer, MD2, H. Lerche, MD1, U.B.S. Hedrich, PhD1
1Dept. of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; 2 Department of Neuropediatrics, University Medical Clinic Giessen, Germany; 3 Epilepsy Center Kork, Kehl-Kork, Germany; 4 Department of Pediatric Neurology, Children’s Hospital, Helsinki University Hospital, Helsinki, Finland; 5 CeGaT GmbH; Dept. of Neurology with focus on Neurodegeneration, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; 6 Hertie Institute for Clinical Brain Research, University of Tübingen, and German Center for Neurodegenerative Diseases (DZNE) Tübingen, Germany; 7 Folkhälsan Institute of Genetics, Neuroscience Center and Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
Corresponding author: Prof. Dr. Holger Lerche
Department of Neurology and Epileptology,
Hertie Institute for Clinical Brain Research,
University of Tübingen,
Hoppe-Seyler-Str. 3
72076 Tübingen, Germany
Detailed clinical case descriptions.
Patient #1 was born in 2004 as the first child of healthy Finnish parents with a negative family history of migraine or other paroxysmal disorders (except maternal grandmother having Menière’s disease, Fig. 1a). Pregnancy and birth were normal. Seizures started at two days old and were described as paroxysmal cyanosis and tremor. EEG was slightly abnormal at conceptional age of 42 weeks after several epileptic seizures: in quiet sleep, the trace was discontinuous and there were scattered sharp waves. Two days later the EEG had improved to be continuous, but still showed scattered sharp waves. Further seizures were tonic-clonic starting with hypomotor behaviour, and were resistant to phenobarbitone (PB). Adjunctive valproate (VPA) was started at three months. Thereafter, PB was tapered and it was continued with VPA monotherapy except for a 10-months drug-free period.
Symptoms of paroxysmal dizziness with poor balance started at 3.7 years occurring 1-2 times per month. The episodes were associated with slurring of speech and ataxia, nausea and headache since age of 4.5 years, lasted minutes to hours and were provoked by physical exercise and possibly by infections. A trial with acetazolamide had no effect. At four years old, repeated EEG and MRI were normal. He walked independently at 16 months old. At two years of age, he showed skills at the 18 month level (Bayley-II). The latest neuropsychological evaluation at 10 years old disclosed a verbal IQ of 72 and a performance IQ of 67 (WISC IV). The patient’s intellectual development has progressed steadily during his neuropsychological follow-up since age two years. Physical exam at age 15 years showed motor clumsiness and double ankle reflexes bilaterally (meaning two jerks after one tap).
Patient #2 was born in 2006 as only child of healthy non-consanguineous German parents (Fig. 1b). Pregnancy was complicated by insulin-dependent gestational diabetes of the mother and premature labour since the 28th gestational week. Normal birth was given after 35 weeks. Multifocal clonic and bilateral tonic-clonic seizures lasting 10-120 seconds started in the fourth week of life, and were well controlled by PB. One interictal EEG showed bilateral central sharp waves, while all other EEGs registered gave normal results. The girl’s further course was uncomplicated until a series of generalized tonic-clonic seizures during a febrile infection at five months old, necessitating intravenous treatment with clonazepam and phenytoin on the intensive care unit. VPA was added and PB was slowly tapered off. No further seizures occurred after the age of 5 months, and VPA was finally discontinued at age 7 years. The girl reached early motor and mental milestones in time, and attended a regular kindergarten.
From 20 months of age on, episodes clearly different from the initial seizures were noticed, increasing in frequency and severity with time. These attacks are characterized by headache, slurred speech, impaired balance and ataxic gait. During these episodes, she refuses to walk, but remains able to crawl or to shuffle on her buttocks. No nystagmus is visible. The attacks occur 1-10 times per week for 1-5 minutes, but occasionally continue with fluctuating symptoms up to two hours.
Discontinuation of VPA at 7 years neither influenced the frequency of ataxic episodes nor led to reoccurrence of seizures. At last follow-up at age 8 years, she was drug-free. Neurological examination at this time revealed motor dyspraxia and clumsiness, but no signs of permanent ataxia. She attends regular elementary school.
Patient #3, carrying the same de novo missense SCN2A mutation as the previously described patient #4 [1] (p.Ala263Val, A263V), is the only child of healthy German parents born in 2011 (Fig. 1c). His maternal aunt had epilepsy with neonatal onset, but no further information was available. Pregnancy was uneventful until caesarean section with 40+3 gestational weeks due to a pathologic cardiotocogram. Immediately after birth (pH 7.35, Apgar 10/10), a marked muscular hypotonia and sleepiness were recognized. The hypotonia persisted but improved in the second year of life. His development was only slightly retarded, as documented by psychological evaluations at age 5 and 8 months.
A first cluster of bilateral tonic seizures occurred at 7 days of life. Treatment with vitamin B6, PB, levetiracetam (LEV), and topiramate (TPM) failed to control further clusters that lasted for 2-3 days and presented with series of bilateral asymmetric tonic and tonic-clonic seizures. The maximal seizure-free interval was five weeks. Early interictal EEGs were normal. Oxcarbazepine (OXC) was added to LEV at 4 months of age and the patient remained free from epileptic seizures from 7 months on. Two brain MRIs at three weeks and 6 months of age and broad neurometabolic work-up revealed normal results. Between 4 and 17 months, EEGs showed rare bilateral multifocal sharp-waves with temporo-occipital maxima. Right frontocentral sharp-waves occurred at age 17 months and persisted until today. LEV was stopped at the age of 18 months.
A first, more nonspecific attack was noticed at the age of 15 months when the patient was completely motionless during a mild febrile infection. At the age of 22 months, the parents reported an episode of ataxia. Mild symptoms started in the morning and in the afternoon, he was not able to walk or stand. Further similar attacks occurred every 10 to 14 days, lasted for hours up to the whole day and disappeared overnight. An “ictal” video-EEG was normal. Videos demonstrated a clear ataxic gait while the boy was completely responsive. However, he did not show extremity tremor or nystagmus. Additionally, he had no symptoms unambiguously suspect for pain. Only two episodes at age 23 and 27 months were accompanied by continuous crying and touch-sensitivity. Increasing the OXC dose was ineffective and the medication was slowly changed to lamotrigine (LTG) starting at 3.5 years. The patient remained seizure-free, but the frequency of the ataxic attacks is still unchanged. Only the severity of the symptoms was slightly reduced with LTG.
Patient #4 was born in 1999 and has a positive history for migraine with visual aura (for pedigree see [1]). He is carrier of the de novo missense SCN2A mutation p.Ala263Val (A263V) and presented with neonatal-onset seizures with hypomotor semiology followed by tonic-clonic seizures as described previously [1]. During treatment with phenytoin (PHT), the patient’s seizures reduced markedly at 13 months old. Since then, he has suffered from three isolated generalized tonic-clonic seizures, at 3.5, at 6.5 and at 14.5 years of age under different medications (lastly LTG, see below). The habitual headache-ataxia episodes started at 18 months old and were pharmacoresistant [1] until today (now 16 years old) recurring one to three times per month. After this patient was reported in 2010 (online video published in [1]) he has tried 4-aminopyridine (Fampyra, 10 mg/d for 12 days), propranolol (max. 40 mg tid) for seven months and TPM for ten months. He is currently on LTG monotherapy (300 mg/d). None of these drugs have reduced the frequency of his episodes. Mild clonus of the right ankle has been noted during the last six months. At the latest cognitive testing (WISC-IV) at 15 years, his verbal IQ was 76 and performance IQ 71. The most pronounced deficits were poor visuospatial abilities and marked dyspraxia both in manual coordination and speech.
Supplemental reference:
1. Liao Y, Anttonen AK, Liukkonen E, et al. SCN2A mutation associated with neonatal epilepsy, late-onset episodic ataxia, myoclonus, and pain. Neurology 2010;75(16):1454-8 doi: 10.1212/WNL.0b013e3181f8812e[published Online First: Epub Date]|.
Supplementary figure
Supplementary Fig. S1: Further electrophysiological parameters. (a) Voltage dependence of persistent sodium currents showing no significant difference between WT and mutant channels. Current amplitudes were recorded at the end of a 70 ms depolarization to the indicated potentials and are normalized to the peak amplitude (steady state current/initial peak current). (b) Voltage dependence of the fast inactivation time constant, τh, determined by second order exponential fits to the current decay. There was no significant difference between WT and mutant channels at any test voltage.