The phenotypic spectrum of SCN8A encephalopathy

Jan Larsen, Gemma L Carvill, Elena Gardella, Gerhard Kluger, Gudrun Schmiedel, Nina Barisic, Christel Depienne, Eva Brilstra, Yuan Mang, Jens Erik Klint Nielsen, Martin Kirkpatrick, David Goudie, Rebecca Goldman, Johanna A Jähn, Birgit Jepsen, Deepak Gill, Miriam Döcker, Saskia Biskup, Jacinta M McMahon, Bobby KoelemanMandy Harris, Kees Braun, Carolien G F de Kovel, Carla Marini, Nicola Specchio, Tania Djémié, Sarah Weckhuysen, Niels Tommerup, Monica Troncoso, Ledia Troncoso, Andrea Bevot, Markus Wolff, Helle Hjalgrim, Renzo Guerrini, Ingrid E Scheffer, Heather C Mefford, Rikke S Møller, EuroEPINOMICS RES Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations.

METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data.

RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges.

CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.

OriginalsprogEngelsk
TidsskriftNeurology
Vol/bind84
Udgave nummer5
Sider (fra-til)480-9
ISSN0028-3878
DOI
StatusUdgivet - 3. feb. 2015

Fingeraftryk

Epilepsy, Partial, Motor
Mutation
Muscle Hypotonia
Electroencephalography
Absence Epilepsy
Abnormal Reflexes
Mosaicism
Movement Disorders
Sequence Analysis

Citer dette

Larsen, J., Carvill, G. L., Gardella, E., Kluger, G., Schmiedel, G., Barisic, N., ... EuroEPINOMICS RES Consortium (2015). The phenotypic spectrum of SCN8A encephalopathy. Neurology, 84(5), 480-9. https://doi.org/10.1212/WNL.0000000000001211
Larsen, Jan ; Carvill, Gemma L ; Gardella, Elena ; Kluger, Gerhard ; Schmiedel, Gudrun ; Barisic, Nina ; Depienne, Christel ; Brilstra, Eva ; Mang, Yuan ; Nielsen, Jens Erik Klint ; Kirkpatrick, Martin ; Goudie, David ; Goldman, Rebecca ; Jähn, Johanna A ; Jepsen, Birgit ; Gill, Deepak ; Döcker, Miriam ; Biskup, Saskia ; McMahon, Jacinta M ; Koeleman, Bobby ; Harris, Mandy ; Braun, Kees ; de Kovel, Carolien G F ; Marini, Carla ; Specchio, Nicola ; Djémié, Tania ; Weckhuysen, Sarah ; Tommerup, Niels ; Troncoso, Monica ; Troncoso, Ledia ; Bevot, Andrea ; Wolff, Markus ; Hjalgrim, Helle ; Guerrini, Renzo ; Scheffer, Ingrid E ; Mefford, Heather C ; Møller, Rikke S ; EuroEPINOMICS RES Consortium. / The phenotypic spectrum of SCN8A encephalopathy. I: Neurology. 2015 ; Bind 84, Nr. 5. s. 480-9.
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title = "The phenotypic spectrum of SCN8A encephalopathy",
abstract = "OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations.METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data.RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges.CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.",
keywords = "Adolescent, Brain Diseases, Child, Child, Preschool, Electroencephalography, Epilepsy, Female, Follow-Up Studies, Humans, Infant, Internationality, Male, Mutation, NAV1.6 Voltage-Gated Sodium Channel, Phenotype",
author = "Jan Larsen and Carvill, {Gemma L} and Elena Gardella and Gerhard Kluger and Gudrun Schmiedel and Nina Barisic and Christel Depienne and Eva Brilstra and Yuan Mang and Nielsen, {Jens Erik Klint} and Martin Kirkpatrick and David Goudie and Rebecca Goldman and J{\"a}hn, {Johanna A} and Birgit Jepsen and Deepak Gill and Miriam D{\"o}cker and Saskia Biskup and McMahon, {Jacinta M} and Bobby Koeleman and Mandy Harris and Kees Braun and {de Kovel}, {Carolien G F} and Carla Marini and Nicola Specchio and Tania Dj{\'e}mi{\'e} and Sarah Weckhuysen and Niels Tommerup and Monica Troncoso and Ledia Troncoso and Andrea Bevot and Markus Wolff and Helle Hjalgrim and Renzo Guerrini and Scheffer, {Ingrid E} and Mefford, {Heather C} and M{\o}ller, {Rikke S} and {EuroEPINOMICS RES Consortium}",
note = "{\circledC} 2015 American Academy of Neurology.",
year = "2015",
month = "2",
day = "3",
doi = "10.1212/WNL.0000000000001211",
language = "English",
volume = "84",
pages = "480--9",
journal = "Neurology",
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Larsen, J, Carvill, GL, Gardella, E, Kluger, G, Schmiedel, G, Barisic, N, Depienne, C, Brilstra, E, Mang, Y, Nielsen, JEK, Kirkpatrick, M, Goudie, D, Goldman, R, Jähn, JA, Jepsen, B, Gill, D, Döcker, M, Biskup, S, McMahon, JM, Koeleman, B, Harris, M, Braun, K, de Kovel, CGF, Marini, C, Specchio, N, Djémié, T, Weckhuysen, S, Tommerup, N, Troncoso, M, Troncoso, L, Bevot, A, Wolff, M, Hjalgrim, H, Guerrini, R, Scheffer, IE, Mefford, HC, Møller, RS & EuroEPINOMICS RES Consortium 2015, 'The phenotypic spectrum of SCN8A encephalopathy', Neurology, bind 84, nr. 5, s. 480-9. https://doi.org/10.1212/WNL.0000000000001211

The phenotypic spectrum of SCN8A encephalopathy. / Larsen, Jan; Carvill, Gemma L; Gardella, Elena; Kluger, Gerhard; Schmiedel, Gudrun; Barisic, Nina; Depienne, Christel; Brilstra, Eva; Mang, Yuan; Nielsen, Jens Erik Klint; Kirkpatrick, Martin; Goudie, David; Goldman, Rebecca; Jähn, Johanna A; Jepsen, Birgit; Gill, Deepak; Döcker, Miriam; Biskup, Saskia; McMahon, Jacinta M; Koeleman, Bobby; Harris, Mandy; Braun, Kees; de Kovel, Carolien G F; Marini, Carla; Specchio, Nicola; Djémié, Tania; Weckhuysen, Sarah; Tommerup, Niels; Troncoso, Monica; Troncoso, Ledia; Bevot, Andrea; Wolff, Markus; Hjalgrim, Helle; Guerrini, Renzo; Scheffer, Ingrid E; Mefford, Heather C; Møller, Rikke S; EuroEPINOMICS RES Consortium.

I: Neurology, Bind 84, Nr. 5, 03.02.2015, s. 480-9.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - The phenotypic spectrum of SCN8A encephalopathy

AU - Larsen, Jan

AU - Carvill, Gemma L

AU - Gardella, Elena

AU - Kluger, Gerhard

AU - Schmiedel, Gudrun

AU - Barisic, Nina

AU - Depienne, Christel

AU - Brilstra, Eva

AU - Mang, Yuan

AU - Nielsen, Jens Erik Klint

AU - Kirkpatrick, Martin

AU - Goudie, David

AU - Goldman, Rebecca

AU - Jähn, Johanna A

AU - Jepsen, Birgit

AU - Gill, Deepak

AU - Döcker, Miriam

AU - Biskup, Saskia

AU - McMahon, Jacinta M

AU - Koeleman, Bobby

AU - Harris, Mandy

AU - Braun, Kees

AU - de Kovel, Carolien G F

AU - Marini, Carla

AU - Specchio, Nicola

AU - Djémié, Tania

AU - Weckhuysen, Sarah

AU - Tommerup, Niels

AU - Troncoso, Monica

AU - Troncoso, Ledia

AU - Bevot, Andrea

AU - Wolff, Markus

AU - Hjalgrim, Helle

AU - Guerrini, Renzo

AU - Scheffer, Ingrid E

AU - Mefford, Heather C

AU - Møller, Rikke S

AU - EuroEPINOMICS RES Consortium

N1 - © 2015 American Academy of Neurology.

PY - 2015/2/3

Y1 - 2015/2/3

N2 - OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations.METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data.RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges.CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.

AB - OBJECTIVE: SCN8A encodes the sodium channel voltage-gated α8-subunit (Nav1.6). SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. We aimed to delineate the phenotype associated with SCN8A mutations.METHODS: We used high-throughput sequence analysis of the SCN8A gene in 683 patients with a range of epileptic encephalopathies. In addition, we ascertained cases with SCN8A mutations from other centers. A detailed clinical history was obtained together with a review of EEG and imaging data.RESULTS: Seventeen patients with de novo heterozygous mutations of SCN8A were studied. Seizure onset occurred at a mean age of 5 months (range: 1 day to 18 months); in general, seizures were not triggered by fever. Fifteen of 17 patients had multiple seizure types including focal, tonic, clonic, myoclonic and absence seizures, and epileptic spasms; seizures were refractory to antiepileptic therapy. Development was normal in 12 patients and slowed after seizure onset, often with regression; 5 patients had delayed development from birth. All patients developed intellectual disability, ranging from mild to severe. Motor manifestations were prominent including hypotonia, dystonia, hyperreflexia, and ataxia. EEG findings comprised moderate to severe background slowing with focal or multifocal epileptiform discharges.CONCLUSION: SCN8A encephalopathy presents in infancy with multiple seizure types including focal seizures and spasms in some cases. Outcome is often poor and includes hypotonia and movement disorders. The majority of mutations arise de novo, although we observed a single case of somatic mosaicism in an unaffected parent.

KW - Adolescent

KW - Brain Diseases

KW - Child

KW - Child, Preschool

KW - Electroencephalography

KW - Epilepsy

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Infant

KW - Internationality

KW - Male

KW - Mutation

KW - NAV1.6 Voltage-Gated Sodium Channel

KW - Phenotype

U2 - 10.1212/WNL.0000000000001211

DO - 10.1212/WNL.0000000000001211

M3 - Journal article

C2 - 25568300

VL - 84

SP - 480

EP - 489

JO - Neurology

JF - Neurology

SN - 0028-3878

IS - 5

ER -

Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N et al. The phenotypic spectrum of SCN8A encephalopathy. Neurology. 2015 feb 3;84(5):480-9. https://doi.org/10.1212/WNL.0000000000001211