Acta Neurol Belg DOI 10.1007/s13760-015-0454-8
LETTER TO THE EDITOR
De novo R853Q mutation of SCN2A gene and West syndrome Debopam Samanta1 • Raghu Ramakrishnaiah2
Received: 20 February 2015 / Accepted: 28 February 2015 Ó Belgian Neurological Society 2015
Introduction SCN2A mutations can cause benign familial neonatal–infantile seizures and various epileptic encephalopathies. We report an infant with de novo SCN2A mutation, who presented with epileptic spasms, and later developed focal and myoclonic seizures. This report highlights the importance of genomic screening in patients with West syndrome (WS), emergence of a broad phenotype of SCN2A mutations, and importance of further investigation of the genotype–phenotype correlation of mutations to advance our understanding of pathophysiologic mechanism of seizures.
Patient description An 8-month-old boy with history of laryngomalacia and developmental delay transferred to our hospital with concern of seizure-like activity for 2 days. He was a product of normal pregnancy and was born at term via cesarean section due to breech presentation. There were no known prenatal, perinatal, or postnatal complications. No family history of any neurological disorders was present. Patient had delayed attainment of development in head control, babbling, and ability to push his head up with his arm when
& Debopam Samanta [email protected] 1
Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2
Division of Neuroradiology and Pediatric Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
in prone position. He had started to roll over, but stopped doing that few weeks prior to his presentation. He could not hold objects in his hands or sit-up unassisted. He was alert but irritable. No cranial nerve deficit was seen. Tone was diffusely low but no focal weakness was appreciated. Clusters of epileptic spasms were observed during admission. EEG revealed very high voltage, irregular, asynchronous delta slow waves associated with multifocal spikes consistent with hypsarrythmia (Fig. 1a). Video EEG captured multiple episodes of brief flexion of neck, mild abduction of bilateral arms, and up rolling of eyes with sudden and diffuse burst of sharply contoured delta activities followed by background attenuation in the EEG. He was initially treated with pyridoxine and vigabatrin. His spasms were intractable to these agents and ACTH injection was tried which provided remission of the spasms. He soon had recurrence of seizures in the form of focal (Fig. 1b) and myoclonic seizures and remained intractable to levetiracetam, topiramate, clonazepam, clobazam, lamotrigine, and ketogenic diet. Follow-up over more than 1.5 years revealed progressive decrease in head circumference and severe developmental delay. He also developed choreiform and dystonic hyperkinetic movements. Brain magnetic resonance imaging showed progressive global atrophy and signal abnormality in the basal ganglia and thalamus (Fig. 2). Extensive metabolic testing which includes renal panel with electrolytes, glucose, liver panel, serum electrolytes, urinalysis, serum lactate and pyruvate, plasma ammonia, urine organic acids, serum and urine organic acids, and serum biotinidase was normal. CSF was evaluated for cell count, chemistry, lactate, pyruvate, amino acids and neurotransmitters, and did not show any abnormality. Chromosomal microarray and mitochondrial whole genome sequence analysis did not reveal any diagnosis. Commercial testing for genetic
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Acta Neurol Belg
Fig. 1 a Hypsarrythmia. Sensitivity 10 lv/mm. b Focal seizure with ictal discharge (rhythmic sharply contoured, 0.5–1 Hz, high amplitude delta activities) from centroparietal and midline regions
epilepsies identified the patient as the heterozygous for the de novo R853Q mutation (c.2558 G[A) in the SCN2A gene. Parents were tested negative for the mutation.
Discussion The West syndrome (WS) is an epileptic encephalopathy and associates with epileptic spasms, a hypsarrythmia EEG pattern, and developmental regression. Several genetic based conditions such as mutations of CDKL-5, ARX, and, KCNQ2 genes are associated with epileptic spasms [1]. Developmental desynchronization model due to mutation
123
in the gene governing ontogenesis or other neuromodulators had been proposed [2]. The subunit of voltage gated sodium channel is composed of four domains (I–IV). Each domain contains five hydrophobic segments and one positively charged segment (S4). The particular type of voltage-gated sodium channel, Nav 1.2, is encoded by SCN2A gene; it is highly expressed in the brain during early development. Majority of the patients with mutations in SCN2A present with focal seizures between 2 days and 7 months of age. These patients with benign familial neonatal-infantile seizures (BFNIS) have excellent prognosis with seizure remission typically before 13 months of age. More recently, SCN2A mutation
Acta Neurol Belg Fig. 2 Axial T2 weighted image (a) from the initial MRI study which showed no significant abnormality. A follow-up MRI at 3-month interval showed global cerebral parenchymal atrophy. Axial T2 weighted image (b) shows exvacuo ventricular dilatation and sulcal prominence secondary to parenchymal atrophy. The hyperintensity within the globus pallidus (white arrows) on axial T2 WI (b) and coronal FLAIR (c) images. The thalamus also showed signal abnormality (black arrows). The axial B1000 image show restricted diffusivity within the basal ganglia corresponding to the signal changes on the T2 and FLAIR sequences
had been found to be associated with epileptic encephalopathy, most specifically with Ohtahara syndrome. Pathogenic mutations by changing net excitability of neurons cause epileptic encephalopathies. Only one patient with the de novo R853Q mutation in the SCN2A gene was previously reported in association with WS [3]. That patient presented at 10 months of age with spasms. He also had severe developmental delay, cerebral and cerebellar atrophy, and a thin corpus callosum. We report the 2nd case of WS with de novo SCN2A gene mutation. Our patient had choreiform and dystonic hyperkinetic movements and abnormal basal ganglia involvement in the MRI. Though, it can be a novel imaging finding with this entity, undiagnosed metabolic disorder, seizure or hypoxia related secondary injury cannot be completely excluded. The R853Q mutation substitutes a non-conservative amino acid and likely impacts secondary protein structure. This report expands our understanding of genetic basis of WS. This case also confirms previous finding of WS secondary to mutation in a positively charged segment
(S4) of domain II, contrary to most patients with Ohtahara syndrome, who have mutations found in the linkers between transmembrane regions of Nav1.2, especially between S4 and S5 domain III. Though mutation in one gene can cause wide phenotypic spectrum, investigation of the genotype–phenotype correlation of mutations may contribute to our understanding of pathophysiologic mechanism of seizures between different epileptic encephalopathies. SCN2A mutations causing benign epilepsies tend to be located in transmembrane regions but mutations causing intractable epilepsies are usually found outside the transmembrane domains. Our study is limited—though neither parent was found to carry the R853Q mutation, possibility of germline mosaicism cannot be excluded, and known or expected pathogenic variants may be present in a portion of the gene, not covered and detected by the test. Acknowledgments The authors received no financial support for the research, authorship, and/or publication of this article.
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Acta Neurol Belg Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical statement Highest ethical standard is maintained during the study. Parents’ informed consent is taken.
References 1. Samanta D, Ramakrishnaiah R, Willis E, Frye RE (2014) Myoclonic epilepsy evolved into West syndrome: a patient with
123
a novel de novo KCNQ2 mutation. Acta Neurol Belg PMID: 25092550 2. Frost JD Jr, Hrachovy RA (2005) Pathogenesis of infantile spasms: a model based on developmental desynchronization. J Clin Neurophysiol 22(1):25–36 3. Nakamura K, Kato M, Osaka H et al (2013) Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81(11):992–998
LETTER TO THE EDITOR
De novo R853Q mutation of SCN2A gene and West syndrome Debopam Samanta1 • Raghu Ramakrishnaiah2
Received: 20 February 2015 / Accepted: 28 February 2015 Ó Belgian Neurological Society 2015
Introduction SCN2A mutations can cause benign familial neonatal–infantile seizures and various epileptic encephalopathies. We report an infant with de novo SCN2A mutation, who presented with epileptic spasms, and later developed focal and myoclonic seizures. This report highlights the importance of genomic screening in patients with West syndrome (WS), emergence of a broad phenotype of SCN2A mutations, and importance of further investigation of the genotype–phenotype correlation of mutations to advance our understanding of pathophysiologic mechanism of seizures.
Patient description An 8-month-old boy with history of laryngomalacia and developmental delay transferred to our hospital with concern of seizure-like activity for 2 days. He was a product of normal pregnancy and was born at term via cesarean section due to breech presentation. There were no known prenatal, perinatal, or postnatal complications. No family history of any neurological disorders was present. Patient had delayed attainment of development in head control, babbling, and ability to push his head up with his arm when
& Debopam Samanta [email protected] 1
Neurology Section, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, USA
2
Division of Neuroradiology and Pediatric Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA
in prone position. He had started to roll over, but stopped doing that few weeks prior to his presentation. He could not hold objects in his hands or sit-up unassisted. He was alert but irritable. No cranial nerve deficit was seen. Tone was diffusely low but no focal weakness was appreciated. Clusters of epileptic spasms were observed during admission. EEG revealed very high voltage, irregular, asynchronous delta slow waves associated with multifocal spikes consistent with hypsarrythmia (Fig. 1a). Video EEG captured multiple episodes of brief flexion of neck, mild abduction of bilateral arms, and up rolling of eyes with sudden and diffuse burst of sharply contoured delta activities followed by background attenuation in the EEG. He was initially treated with pyridoxine and vigabatrin. His spasms were intractable to these agents and ACTH injection was tried which provided remission of the spasms. He soon had recurrence of seizures in the form of focal (Fig. 1b) and myoclonic seizures and remained intractable to levetiracetam, topiramate, clonazepam, clobazam, lamotrigine, and ketogenic diet. Follow-up over more than 1.5 years revealed progressive decrease in head circumference and severe developmental delay. He also developed choreiform and dystonic hyperkinetic movements. Brain magnetic resonance imaging showed progressive global atrophy and signal abnormality in the basal ganglia and thalamus (Fig. 2). Extensive metabolic testing which includes renal panel with electrolytes, glucose, liver panel, serum electrolytes, urinalysis, serum lactate and pyruvate, plasma ammonia, urine organic acids, serum and urine organic acids, and serum biotinidase was normal. CSF was evaluated for cell count, chemistry, lactate, pyruvate, amino acids and neurotransmitters, and did not show any abnormality. Chromosomal microarray and mitochondrial whole genome sequence analysis did not reveal any diagnosis. Commercial testing for genetic
123
Acta Neurol Belg
Fig. 1 a Hypsarrythmia. Sensitivity 10 lv/mm. b Focal seizure with ictal discharge (rhythmic sharply contoured, 0.5–1 Hz, high amplitude delta activities) from centroparietal and midline regions
epilepsies identified the patient as the heterozygous for the de novo R853Q mutation (c.2558 G[A) in the SCN2A gene. Parents were tested negative for the mutation.
Discussion The West syndrome (WS) is an epileptic encephalopathy and associates with epileptic spasms, a hypsarrythmia EEG pattern, and developmental regression. Several genetic based conditions such as mutations of CDKL-5, ARX, and, KCNQ2 genes are associated with epileptic spasms [1]. Developmental desynchronization model due to mutation
123
in the gene governing ontogenesis or other neuromodulators had been proposed [2]. The subunit of voltage gated sodium channel is composed of four domains (I–IV). Each domain contains five hydrophobic segments and one positively charged segment (S4). The particular type of voltage-gated sodium channel, Nav 1.2, is encoded by SCN2A gene; it is highly expressed in the brain during early development. Majority of the patients with mutations in SCN2A present with focal seizures between 2 days and 7 months of age. These patients with benign familial neonatal-infantile seizures (BFNIS) have excellent prognosis with seizure remission typically before 13 months of age. More recently, SCN2A mutation
Acta Neurol Belg Fig. 2 Axial T2 weighted image (a) from the initial MRI study which showed no significant abnormality. A follow-up MRI at 3-month interval showed global cerebral parenchymal atrophy. Axial T2 weighted image (b) shows exvacuo ventricular dilatation and sulcal prominence secondary to parenchymal atrophy. The hyperintensity within the globus pallidus (white arrows) on axial T2 WI (b) and coronal FLAIR (c) images. The thalamus also showed signal abnormality (black arrows). The axial B1000 image show restricted diffusivity within the basal ganglia corresponding to the signal changes on the T2 and FLAIR sequences
had been found to be associated with epileptic encephalopathy, most specifically with Ohtahara syndrome. Pathogenic mutations by changing net excitability of neurons cause epileptic encephalopathies. Only one patient with the de novo R853Q mutation in the SCN2A gene was previously reported in association with WS [3]. That patient presented at 10 months of age with spasms. He also had severe developmental delay, cerebral and cerebellar atrophy, and a thin corpus callosum. We report the 2nd case of WS with de novo SCN2A gene mutation. Our patient had choreiform and dystonic hyperkinetic movements and abnormal basal ganglia involvement in the MRI. Though, it can be a novel imaging finding with this entity, undiagnosed metabolic disorder, seizure or hypoxia related secondary injury cannot be completely excluded. The R853Q mutation substitutes a non-conservative amino acid and likely impacts secondary protein structure. This report expands our understanding of genetic basis of WS. This case also confirms previous finding of WS secondary to mutation in a positively charged segment
(S4) of domain II, contrary to most patients with Ohtahara syndrome, who have mutations found in the linkers between transmembrane regions of Nav1.2, especially between S4 and S5 domain III. Though mutation in one gene can cause wide phenotypic spectrum, investigation of the genotype–phenotype correlation of mutations may contribute to our understanding of pathophysiologic mechanism of seizures between different epileptic encephalopathies. SCN2A mutations causing benign epilepsies tend to be located in transmembrane regions but mutations causing intractable epilepsies are usually found outside the transmembrane domains. Our study is limited—though neither parent was found to carry the R853Q mutation, possibility of germline mosaicism cannot be excluded, and known or expected pathogenic variants may be present in a portion of the gene, not covered and detected by the test. Acknowledgments The authors received no financial support for the research, authorship, and/or publication of this article.
123
Acta Neurol Belg Conflict of interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Ethical statement Highest ethical standard is maintained during the study. Parents’ informed consent is taken.
References 1. Samanta D, Ramakrishnaiah R, Willis E, Frye RE (2014) Myoclonic epilepsy evolved into West syndrome: a patient with
123
a novel de novo KCNQ2 mutation. Acta Neurol Belg PMID: 25092550 2. Frost JD Jr, Hrachovy RA (2005) Pathogenesis of infantile spasms: a model based on developmental desynchronization. J Clin Neurophysiol 22(1):25–36 3. Nakamura K, Kato M, Osaka H et al (2013) Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 81(11):992–998
