Seizure 26 (2015) 69–71
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Clinical letter
Early-onset movement disorder and epileptic encephalopathy due to de novo dominant SCN8A mutation R. Singh a, S. Jayapal a, S. Goyal b, H. Jungbluth a,c,d, K. Lascelles a,* a
Department of Paediatric Neurology, Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, United Kingdom Neurophysiology Department, Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, United Kingdom c Randall Division of Cell and Molecular Biophysics, King’s College London, United Kingdom d Department of Basic and Clinical Neuroscience, IoPPN, King’s College London, United Kingdom b
A R T I C L E I N F O
Article history: Received 18 November 2014 Received in revised form 27 January 2015 Accepted 29 January 2015
1. Background SCN8A is one of an increasing number of genes encoding neuronal sodium channels associated with early-onset epileptic encephalopathies. The SCN8A-encoded sodium channel alpha subunit Nav1.6 is concentrated at the axon initial segment in both excitatory and inhibitory neurons and nodes of Ranvier in motor neurons, resulting, if mutated, in dysregulation of neuronal excitability and motor dysfunction [1]. SCN8A mutations have been mainly associated with early-onset epileptic encephalopathies, developmental delay and movement disorders. The associated phenotype continues to expand [2–4]. We report a unique phenotype with in utero onset of movement disorder, with evolving epilepsy, epileptic encephalopathy and developmental delay. 2. Case report Our proband was the first child of healthy nonconsanguineous, Caucasian parents born at 40 + 3 weeks gestation by ventouse delivery. He did not require any resuscitation. Growth parameters including head circumference were on the 9th percentile and there was no dysmorphism. His mother had noticed unusual ‘‘drumming’’ in utero movements in the later stages of pregnancy, with normal antenatal scans. Shortly after birth he was noted to have jittery movements and a pathologically exaggerated startle response to tactile and acoustic stimuli, prompting a suspicion of hyperekplexia. At 15 h of age he had an asymmetrical clonic seizure,
* Corresponding author at: Children’s Neurosciences Centre, F01 – Staircase D South Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom. Tel.: +44 2071883997; fax: +44 2071884629. E-mail address: [email protected] (K. Lascelles).
diagnosed clinically, lasting for around 2 min, and requiring admission to the neonatal intensive care unit. His initial amplitude integrated EEG and cerebral function monitor were normal. His EEG on day 4 showed a normal background, 5–8 Hz irregular jittery movements of all four limbs picked up on EMG polygraphy electrodes. These movements were stimulus sensitive and their severity increased when he was distressed. He had occasional sharp transients over the vertex, with no ictal EEG correlate to the jittery movements (Video 1 and Fig. 1). Subsequent overnight video telemetry demonstrated a build up of low voltage fast activity at the centro-parietal regions bilaterally at the onset with augmentation of the jittery movements as seen on EMG polygraph. This is followed by centroparietal evolution of spikes bilaterally during the tonic phase of seizure (witnessed in video as elevation of both his legs) followed by generalisation of spike and wave discharges during the apnoeic phase with post ictal accentuation at the offset (Video 2 and Fig. 2). He went on to develop frequent stereotyped tonic/tonic-clonic seizures progressing to epileptic status. Seizures continued despite treatment. The seizure pattern changed from around 3 months, featuring predominantly tonic seizures later on accompanied by apnoeas requiring multiple paediatric intensive care unit (PICU) admissions. Therapeutic trials with several anticonvulsants including clonazepam, vigabatrin, topiramate, levetiracetam, carabamazepine, sodium valproate, phenobarbital, lacosamide were unsuccessful in terms of seizure control, as was the ketogenic diet. High therapeutic levels of phenytoin (18–20 mg/L) appeared to provide some initial benefit but this was not sustained. He continued to have an exaggerated startle, paroxysmal posturing and jittery movements subsiding in sleep that on clinical and encephalographic grounds were not epileptic in nature. During such episodes he became extremely distressed and appeared to
http://dx.doi.org/10.1016/j.seizure.2015.01.017 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
70
R. Singh et al. / Seizure 26 (2015) 69–71
Fig. 1. EEG at the time of Jittery episode (Video 1).
be in discomfort, resulting in repeated presentations to paediatric emergency services and leading to the consideration of an acute abdomen in the differential diagnosis. He was tried on propranolol, piracetam, gabapentin and clonidine for his persistent and non-ictal jittery movements, with no sustainable effect. He had progressive difficulty feeding requiring gastrostomy insertion. He developed peripheral hypertonia with a generalised paucity and lack of purposeful movements and central hypotonia. He was only intermittently visually responsive and able to smile. His head circumference dropped from the 9th to below 0.4th percentile (43 cm). MRI of the brain at 7 days of age was normal. Repeat neuroimaging including MR spectroscopy at 4 months showed mild cerebellar volume loss with age-appropriate myelination. Extensive metabolic investigations were negative. Mutation screening through a next generation sequencing panel covering 48 genes associated with severe developmental delay and earlyonset epileptic encephalopathies epilepsy identified a de novo dominant SCN8A (c.3979A>G; p.Ile1327Val) mutation. 3. Discussion Over the past year there have been a number of cases of pathogenic SCN8A mutations described including a recent case series of 17 patients [2–4]. The majority of mutations are of de novo inheritance and all the reported pathogenic mutations are distributed throughout the SCN8A gene. The clinical phenotype is characterised by early onset intractable seizures progressing to epileptic encephalopathy and severe disability. Various motor
manifestations have been described including hypotonia, spasticity, dystonia, ataxia and choreoathetosis [2] but in only 1 other patient [3], sharing the same genetic mutation as our case, has a severe early onset movement disorder been described. There does not appear to be any phenotype genotype correlation in the cases reported although our case and the one described by Vaher et al. [3] are strikingly similar. Our patient had a de novo dominant SCN8A mutation, possibly associated with a gain-of-function of the NaV1.6 channel with probable in utero onset of movement disorder. The SCN8A-associated seizure phenotype mainly comprises focal clonic seizures evolving to bilateral convulsive seizures, tonic seizures, tonic clonic seizures, and epileptic spasms. Additionally both convulsive and non convulsive status appear to be common [2]. There do not appear to be any pathognomic interictal EEG abnormalities and in the majority of previously reported cases initial EEG’s (where available) were normal or showed only mild changes. Progressive MRI changes are described in a number of patients with cerebral atrophy and in some cases as in our patient, cerebellar atrophy. Our case illustrates that SCN8A mutations may give rise to pathologically exaggerated startle; increased jitteriness and an early-onset movement disorder even before clinical or electroencephalographic evidence for the more typical epileptic encephalopathy, and have to be considered in the differential diagnosis of non-epileptic hyperexcitability syndromes such as hyperekplexia. Epileptic and non-epileptic manifestations of defective NaV1.6 function in the same child may be difficult to distinguish and pose substantial diagnostic and management challenges. More widely available epilepsy genetic diagnostic
R. Singh et al. / Seizure 26 (2015) 69–71
71
Fig. 2. EEG changes, during video telemetry showing episode of tonic seizures involving both lower limbs, followed by ictal changes (Video 2).
testing is likely to expand the SCN8A-related phenotypical spectrum further and to delineate the associated movement disorder in more detail.
Conflict of interest None of the authors has any conflict of interest to disclose. Acknowledgements We like to thank Natalie Trump and Lucy Jenkins, clinical scientists at the North East Thames Regional Genetic Service, who performed the genetic analysis.
References [1] Chen S, Su H, Yue C, Remy S, Royeck M, Sochivko D, et al. An increase in persistent sodium current contributes to intrinsic neuronal bursting after status epilepticus. J Neurophysiol 2011;105:117–29. [2] Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015. http:// dx.doi.org/10.1212/WNL.0000000000001211. [3] Vaher U, No˜ukas M, Nikopensius T, Kals M, Annilo T, Nelis M, et al. De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders. J Child Neurol 2013;(12):202–6. [4] Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014;55(7):994–1000.
Contents lists available at ScienceDirect
Seizure journal homepage: www.elsevier.com/locate/yseiz
Clinical letter
Early-onset movement disorder and epileptic encephalopathy due to de novo dominant SCN8A mutation R. Singh a, S. Jayapal a, S. Goyal b, H. Jungbluth a,c,d, K. Lascelles a,* a
Department of Paediatric Neurology, Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, United Kingdom Neurophysiology Department, Evelina Children’s Hospital, Guys and St Thomas’ NHS Foundation Trust, United Kingdom c Randall Division of Cell and Molecular Biophysics, King’s College London, United Kingdom d Department of Basic and Clinical Neuroscience, IoPPN, King’s College London, United Kingdom b
A R T I C L E I N F O
Article history: Received 18 November 2014 Received in revised form 27 January 2015 Accepted 29 January 2015
1. Background SCN8A is one of an increasing number of genes encoding neuronal sodium channels associated with early-onset epileptic encephalopathies. The SCN8A-encoded sodium channel alpha subunit Nav1.6 is concentrated at the axon initial segment in both excitatory and inhibitory neurons and nodes of Ranvier in motor neurons, resulting, if mutated, in dysregulation of neuronal excitability and motor dysfunction [1]. SCN8A mutations have been mainly associated with early-onset epileptic encephalopathies, developmental delay and movement disorders. The associated phenotype continues to expand [2–4]. We report a unique phenotype with in utero onset of movement disorder, with evolving epilepsy, epileptic encephalopathy and developmental delay. 2. Case report Our proband was the first child of healthy nonconsanguineous, Caucasian parents born at 40 + 3 weeks gestation by ventouse delivery. He did not require any resuscitation. Growth parameters including head circumference were on the 9th percentile and there was no dysmorphism. His mother had noticed unusual ‘‘drumming’’ in utero movements in the later stages of pregnancy, with normal antenatal scans. Shortly after birth he was noted to have jittery movements and a pathologically exaggerated startle response to tactile and acoustic stimuli, prompting a suspicion of hyperekplexia. At 15 h of age he had an asymmetrical clonic seizure,
* Corresponding author at: Children’s Neurosciences Centre, F01 – Staircase D South Wing, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, United Kingdom. Tel.: +44 2071883997; fax: +44 2071884629. E-mail address: [email protected] (K. Lascelles).
diagnosed clinically, lasting for around 2 min, and requiring admission to the neonatal intensive care unit. His initial amplitude integrated EEG and cerebral function monitor were normal. His EEG on day 4 showed a normal background, 5–8 Hz irregular jittery movements of all four limbs picked up on EMG polygraphy electrodes. These movements were stimulus sensitive and their severity increased when he was distressed. He had occasional sharp transients over the vertex, with no ictal EEG correlate to the jittery movements (Video 1 and Fig. 1). Subsequent overnight video telemetry demonstrated a build up of low voltage fast activity at the centro-parietal regions bilaterally at the onset with augmentation of the jittery movements as seen on EMG polygraph. This is followed by centroparietal evolution of spikes bilaterally during the tonic phase of seizure (witnessed in video as elevation of both his legs) followed by generalisation of spike and wave discharges during the apnoeic phase with post ictal accentuation at the offset (Video 2 and Fig. 2). He went on to develop frequent stereotyped tonic/tonic-clonic seizures progressing to epileptic status. Seizures continued despite treatment. The seizure pattern changed from around 3 months, featuring predominantly tonic seizures later on accompanied by apnoeas requiring multiple paediatric intensive care unit (PICU) admissions. Therapeutic trials with several anticonvulsants including clonazepam, vigabatrin, topiramate, levetiracetam, carabamazepine, sodium valproate, phenobarbital, lacosamide were unsuccessful in terms of seizure control, as was the ketogenic diet. High therapeutic levels of phenytoin (18–20 mg/L) appeared to provide some initial benefit but this was not sustained. He continued to have an exaggerated startle, paroxysmal posturing and jittery movements subsiding in sleep that on clinical and encephalographic grounds were not epileptic in nature. During such episodes he became extremely distressed and appeared to
http://dx.doi.org/10.1016/j.seizure.2015.01.017 1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
70
R. Singh et al. / Seizure 26 (2015) 69–71
Fig. 1. EEG at the time of Jittery episode (Video 1).
be in discomfort, resulting in repeated presentations to paediatric emergency services and leading to the consideration of an acute abdomen in the differential diagnosis. He was tried on propranolol, piracetam, gabapentin and clonidine for his persistent and non-ictal jittery movements, with no sustainable effect. He had progressive difficulty feeding requiring gastrostomy insertion. He developed peripheral hypertonia with a generalised paucity and lack of purposeful movements and central hypotonia. He was only intermittently visually responsive and able to smile. His head circumference dropped from the 9th to below 0.4th percentile (43 cm). MRI of the brain at 7 days of age was normal. Repeat neuroimaging including MR spectroscopy at 4 months showed mild cerebellar volume loss with age-appropriate myelination. Extensive metabolic investigations were negative. Mutation screening through a next generation sequencing panel covering 48 genes associated with severe developmental delay and earlyonset epileptic encephalopathies epilepsy identified a de novo dominant SCN8A (c.3979A>G; p.Ile1327Val) mutation. 3. Discussion Over the past year there have been a number of cases of pathogenic SCN8A mutations described including a recent case series of 17 patients [2–4]. The majority of mutations are of de novo inheritance and all the reported pathogenic mutations are distributed throughout the SCN8A gene. The clinical phenotype is characterised by early onset intractable seizures progressing to epileptic encephalopathy and severe disability. Various motor
manifestations have been described including hypotonia, spasticity, dystonia, ataxia and choreoathetosis [2] but in only 1 other patient [3], sharing the same genetic mutation as our case, has a severe early onset movement disorder been described. There does not appear to be any phenotype genotype correlation in the cases reported although our case and the one described by Vaher et al. [3] are strikingly similar. Our patient had a de novo dominant SCN8A mutation, possibly associated with a gain-of-function of the NaV1.6 channel with probable in utero onset of movement disorder. The SCN8A-associated seizure phenotype mainly comprises focal clonic seizures evolving to bilateral convulsive seizures, tonic seizures, tonic clonic seizures, and epileptic spasms. Additionally both convulsive and non convulsive status appear to be common [2]. There do not appear to be any pathognomic interictal EEG abnormalities and in the majority of previously reported cases initial EEG’s (where available) were normal or showed only mild changes. Progressive MRI changes are described in a number of patients with cerebral atrophy and in some cases as in our patient, cerebellar atrophy. Our case illustrates that SCN8A mutations may give rise to pathologically exaggerated startle; increased jitteriness and an early-onset movement disorder even before clinical or electroencephalographic evidence for the more typical epileptic encephalopathy, and have to be considered in the differential diagnosis of non-epileptic hyperexcitability syndromes such as hyperekplexia. Epileptic and non-epileptic manifestations of defective NaV1.6 function in the same child may be difficult to distinguish and pose substantial diagnostic and management challenges. More widely available epilepsy genetic diagnostic
R. Singh et al. / Seizure 26 (2015) 69–71
71
Fig. 2. EEG changes, during video telemetry showing episode of tonic seizures involving both lower limbs, followed by ictal changes (Video 2).
testing is likely to expand the SCN8A-related phenotypical spectrum further and to delineate the associated movement disorder in more detail.
Conflict of interest None of the authors has any conflict of interest to disclose. Acknowledgements We like to thank Natalie Trump and Lucy Jenkins, clinical scientists at the North East Thames Regional Genetic Service, who performed the genetic analysis.
References [1] Chen S, Su H, Yue C, Remy S, Royeck M, Sochivko D, et al. An increase in persistent sodium current contributes to intrinsic neuronal bursting after status epilepticus. J Neurophysiol 2011;105:117–29. [2] Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015. http:// dx.doi.org/10.1212/WNL.0000000000001211. [3] Vaher U, No˜ukas M, Nikopensius T, Kals M, Annilo T, Nelis M, et al. De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders. J Child Neurol 2013;(12):202–6. [4] Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al. Early onset epileptic encephalopathy caused by de novo SCN8A mutations. Epilepsia 2014;55(7):994–1000.
