A case of recurrent encephalopathy with SCN2A missense mutation

doi:10.1016/j.braindev.2014.10.001

Brain and Development

Volume 37, Issue 6, June 2015, Pages 631-634

https://doi.org/10.1016/j.braindev.2014.10.001 Get rights and content

Abstract

Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Mutations in SCN2A, which encodes the Na⁺ channel Na_v1.2, cause epilepsy syndromes and predispose children to acute encephalopathy. Here, we report the case of a young male with recurrent acute encephalopathy who carried a novel missense mutation in the SCN2A gene. He was born by normal delivery and developed repetitive apneic episodes at 2 days of age. Diffusion-weighted imaging revealed high-intensity areas in diffuse subcortical white matter, bilateral thalami, and basal nuclei. His symptoms improved gradually without any specific treatment, but he exhibited a motor milestone delay after the episode. At the age of 10 months, he developed acute cerebellopathy associated with a respiratory syncytial viral infection. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy and seemed to have no obvious sequelae after the episode. He then developed severe diffuse encephalopathy associated with gastroenteritis at the age of 14 months. He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy but was left with severe neurological sequelae. PCR-based analysis revealed a novel de novo missense mutation, c.4979T>G (p.Leu1660Trp), in the SCN2A gene. This case suggests that SCN2A mutations might predispose children to repetitive encephalopathy with variable clinical and imaging findings.

Introduction

Although the precise pathomechanism of acute encephalopathy remains to be elucidated, multiple genetically determined factors might play a role. Mutations in genes such as Ran-binding protein 2 (RANBP2) [1], toll-like receptor 3 (TLR3) [2], and neuronal sodium channel alpha1-subunit (SCN1A) [3], as well as polymorphisms in genes such as carnitine palmitoyltransferase II (CPT2) [4] and adenosine A2A receptor (ADORA2A) [5], are risk factors for multiple syndromes of acute encephalopathy. The etiology and pathophysiology of these syndromes are variable, and the correlation between genotype and phenotype is complex.

Here, we report a patient who presented with recurrent episodes of encephalopathy during the neonatal period and infancy. He had a novel point mutation in the SCN2A gene. This case suggests that SCN2A mutations might predispose neonates and infants to repetitive encephalopathies with variable clinical phenotypes.

Section snippets

Case report

The patient was born by normal delivery from nonconsanguineous parents at 38 weeks of gestation, weighing 2610 g. His Apgar score was 10 after both 1 and 5 min. There was no family history of neurological disorders. He developed repetitive apneic episodes and fatigue at the age of 2 days. At the age of 5 days, diffusion-weighted imaging (DWI) revealed high intensity areas (HIAs) in the diffuse subcortical white matter, bilateral thalami, and basal nuclei (Fig. 1). Examination of the cerebrospinal

Discussion

The clinical course of this patient raised two important clinical issues.

First, some SCN2A mutations may cause repetitive encephalopathy. SCN2A encodes the voltage-gated sodium channel α2-subunit. Previous electrophysiological analyses demonstrated that different mutations have diverse effects on sodium channels. SCN2A mutations were associated with a variety of diseases: benign familial neonatal-infantile seizures, generalized epilepsy with febrile seizures, Dravet syndrome, some intractable

Acknowledgments

We are indebted to all members of the study family for their helpful cooperation. Ms. Minako Yonetani and Akiyo Hamachi for their technical assistance. This work was supported by a Grant-in-Aid for Young Scientists (B) (23791201 to A.I.), Grant-in-Aid for Scientific Research (A) (24249060 to S.H.), Grant-in-Aid for Challenging Exploratory Research (25670481 to S.H.), Bilateral Joint Research Projects (S.H.) from Japan Society for the Promotion of Science (JSPS), Grants for Scientific Research

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Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children
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Clinical spectrum of SCN2A mutations
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2021, Journal of Pediatrics
To describe the features and frequency of respiratory syncytial virus (RSV)-associated severe acute neurologic disease in children.
We performed a systematic review of the literature to identify reports of severe acute neurologic complications associated with acute RSV infection in children aged <15 years (PROSPERO Registration CRD42019125722). Main outcomes included neurologic, clinical, and demographic features of cases and the frequency of disease. We aggregated available case data from the published literature and from the Australian Acute Childhood Encephalitis (ACE) study.
We identified 87 unique studies from 26 countries describing a spectrum of RSV-associated severe acute neurologic syndromes including proven encephalitis, acute encephalopathy, complex seizures, hyponatremic seizures, and immune-mediated disorders. The frequency of RSV infection in acute childhood encephalitis/encephalopathy was 1.2%-6.5%. We aggregated data from 155 individual cases with RSV-associated severe acute neurologic complications; median age was 11.0 months (IQR 2.0-21.5), most were previously healthy (71/104, 68%). Seizure was the most frequently reported neurologic feature (127/150, 85%). RSV was detected in the central nervous system of 12 cases. Most children recovered (81/122, 66%); however, some reports described partial recovery (33/122, 27%) and death (8/122, 7%).
RSV-associated neurologic complications have been widely reported, but there is substantial heterogeneity in the design and quality of existing studies. The findings from our study have implications for the investigation, management, and prevention of RSV-associated neurologic complications. Further, this systematic review can inform the design of future studies aiming to quantify the burden of childhood RSV-associated neurologic disease.
Clinical and genetic spectrum of SCN2A-associated episodic ataxia
2019, European Journal of Paediatric Neurology
Citation Excerpt :
The pathogenic variant p.L1650P found in the three familial cases of EA – lacking epileptic seizures – has been described in a patient with epileptic encephalopathy,26 emphasizing the challenge in genotype–phenotype correlations. A patient with a pathogenic de novo SCN2A missense variant (p.L1660W) affecting this cytoplasmic loop was described with recurrent encephalopathic episodes of which at least one might have been an episode of ataxia.27 Finally, a pathogenic variant in the homologous gene SCN8A at the exact same position as in our three familial cases was described in a patient with epileptic encephalopathy.28
Pathogenic variants in SCN2A are associated with various neurological disorders including epilepsy, autism spectrum disorder and intellectual disability. Few reports have recently described SCN2A-associated episodic ataxia (EA). Our study identifies its broader clinical and genetic spectrum, and describes pharmacological approaches.
We report 21 patients with SCN2A-associated EA, of which 9 are unpublished cases. The large majority of patients present with epileptic seizures (18/21, 86%), often starting within the first three months of life (12/18, 67%). In contrast, onset of episodic ataxia ranged from 10 months to 14 years of age. The frequency of EA episodes ranged from brief, daily events up to 1–2 episodes per year each lasting several weeks. Potential triggers include minor head traumas and sleep deprivation. Cognitive outcome is favorable in most patients with normal or mildly impaired cognitive development in 17/21 patients (81%). No clear genotype–phenotype correlations were identified in this cohort. However, two mutational hotspots were identified, i.e. 7/21 patients (33%) harbor the identical pathogenic variant p.A263V, whereas 5/21 (24%) carry pathogenic variants that affect the S4 segment and its cytoplasmic loop within the domain IV. In addition, we identified six novel pathogenic variants in SCN2A. While acetazolamide was previously reported as beneficial in SCN2A-associated EA in one case, our data show a conflicting response in 8 additional patients treated with acetazolamide: three of them profited from acetazolamide treatment, while 5/8 did not.
Our study describes the heterogeneous clinical spectrum of SCN2A-associated EA, identifies two mutational hotspots and shows positive effects of acetazolamide in about 50%.
Mutations of Voltage-Gated Sodium Channel Genes SCN1A and SCN2A in Epilepsy, Intellectual Disability, and Autism
2016, Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability
Mutations of SCN1A and SCN2A were found in a wide spectrum of epilepsies, intellectual disability, and autism. Nav1.1 protein encoded by SCN1A is densely expressed in parvalbumin-positive inhibitory interneurons and moderately in a subpopulation of excitatory neurons. Dravet syndrome model mice (SCN1A^+/−) showed epileptic seizure, sudden death, and autistic behavior similar to patients, and conditional knockout mice studies revealed that Nav1.1 haploinsufficiency in inhibitory neurons is the primary cause for those features and that in excitatory neurons it is contrarily ameliorating for seizures and sudden death. Whole-exome sequencing studies on hundreds of autistic patients also showed SCN1A de novo loss of function mutations, but those of SCN2A were far more dominated. SCN2A mutations also appear in patients with epileptic encephalopathies, but those are mostly missense suggesting gain-of-function. Dominant expression of Nav1.2 encoded by SCN2A in excitatory neurons may explain the afebrile nature of the disease and suggest distinct pathological cascades for those with SCN1A mutations.
De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
2016, American Journal of Human Genetics
Citation Excerpt :
Her clinical features included hypotonia, moderate intellectual disability, severe behavioral issues and seizures, dysmorphic features, GERD, developmental hip dysplasia, and severe vesicoureteral reflux requiring surgery. A brain MRI obtained at 1 year and 2 months showed a thin corpus callosum, a diminished cerebellar vermis with deep fissures, and significantly diminished white matter volume—findings not reported in prior studies of SCN2A.23,24 Subject 5 is a 12-year, 8-month-old Dutch male (reported previously by Bosch et al. as patient 22) with a de novo c.4293C>A change in RERE that results in the same amino acid change, p.His1431Gln, caused by the c.4293C>G change documented in subject 4.25
Deletions of chromosome 1p36 affect approximately 1 in 5,000 newborns and are associated with developmental delay, intellectual disability, and defects involving the brain, eye, ear, heart, and kidney. Arginine-glutamic acid dipeptide repeats (RERE) is located in the proximal 1p36 critical region. RERE is a widely-expressed nuclear receptor coregulator that positively regulates retinoic acid signaling. Animal models suggest that RERE deficiency might contribute to many of the structural and developmental birth defects and medical problems seen in individuals with 1p36 deletion syndrome, although human evidence supporting this role has been lacking. In this report, we describe ten individuals with intellectual disability, developmental delay, and/or autism spectrum disorder who carry rare and putatively damaging changes in RERE. In all cases in which both parental DNA samples were available, these changes were found to be de novo. Associated features that were recurrently seen in these individuals included hypotonia, seizures, behavioral problems, structural CNS anomalies, ophthalmologic anomalies, congenital heart defects, and genitourinary abnormalities. The spectrum of defects documented in these individuals is similar to that of a cohort of 31 individuals with isolated 1p36 deletions that include RERE and are recapitulated in RERE-deficient zebrafish and mice. Taken together, our findings suggest that mutations in RERE cause a genetic syndrome and that haploinsufficiency of RERE might be sufficient to cause many of the phenotypes associated with proximal 1p36 deletions.
Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures
2015, Epilepsy Research
Citation Excerpt :
Several de novo SCN2A mutations have been reported in severer phenotypes such as DS (Shi et al., 2009) and early-onset epileptic encephalopathy including Ohtahara syndrome (Nakamura et al., 2013). On the other hand, missense SCN2A mutations have recently been identified in a patient with acute encephalitis with refractory, repetitive partial seizures (AERRPS), a typical syndrome of AEIMSE (Kobayashi et al., 2012), and in a patient with recurrent acute encephalopathy (Fukasawa et al., 2015). To elucidate the genetic basis of AESD, we conducted an analysis of the SCN1A and SCN2A genes.
Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood encephalopathy following severe febrile seizures. The pathogenesis of AESD is considered to be fever-induced seizure susceptibility and excitotoxicity, which may be caused by sodium channel dysfunction in some cases. Here we studied whether mutations in genes encoding sodium channels, SCN1A and SCN2A, predispose children to AESD.
We recruited 92 AESD patients in a nationwide survey of acute encephalopathy in Japan from 2008 to 2011. We collected their genomic DNA samples, and sequenced the entire coding region of SCN1A and SCN2A.
Five out of 92 patients (5.4%) had missense mutations either in SCN1A or SCN2A. After a preceding infection with fever, all the patients showed status epilepticus at the onset. Hemiconvulsion–hemiplegia was recognized in three patients during the acute/subacute phase. One patient had taken theophylline for the treatment of bronchial asthma just before the onset of AESD. Familial history was not remarkable except one patient with a SCN1A mutation (G1647S) whose mother had a similar episode of AESD in her childhood. A different substitution (G1674R) at the same amino acid position, as well as two other SCN1A mutations found in this study, had previously been reported in Dravet syndrome. Another SCN1A mutation (R1575C) had been detected in other types of acute encephahlitis/encephalopathy. One patient had SCN2A mutation, F328V, which had previously been reported in Dravet syndrome. Another SCN2A mutation, I172V, was novel. None of the patients were diagnosed with Dravet syndrome or genetic (generalized) epilepsy with febrile seizure plus in the following-up period.
Mutations in SCN1A and SCN2A are a predisposing factor of AESD. Altered channel activity caused by these mutations may provoke seizures and excitotoxic brain damage.
Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review
2023, Movement Disorders Clinical Practice

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Brain and Development

Abstract

Introduction

Section snippets

Case report

Discussion

Acknowledgments

References (10)

Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2

Am J Hum Genet

A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy

Clin Immunol

Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children

Brain Dev

Clinical spectrum of SCN2A mutations

Brain Dev

Acute encephalopathy with a novel point mutation in the SCN2A gene

Epilepsy Res

Cited by (19)

Respiratory Syncytial Virus–Associated Neurologic Complications in Children: A Systematic Review and Aggregated Case Series

Clinical and genetic spectrum of SCN2A-associated episodic ataxia

Mutations of Voltage-Gated Sodium Channel Genes SCN1A and SCN2A in Epilepsy, Intellectual Disability, and Autism

De Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions

Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures

Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review

Case ReportA case of recurrent encephalopathy with SCN2A missense mutation

Abstract

Introduction

Section snippets

Case report

Discussion

Acknowledgments

Am J Hum Genet

Clin Immunol

Brain Dev

Brain Dev

Epilepsy Res

Case Report
A case of recurrent encephalopathy with SCN2A missense mutation