Case ReportA case of recurrent encephalopathy with SCN2A missense mutation
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
References (10)
- et al.
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
(2009) - et al.
A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy
Clin Immunol
(2006) - et al.
Thermolabile CPT II variants and low blood ATP levels are closely related to severity of acute encephalopathy in Japanese children
Brain Dev
(2012) - et al.
Clinical spectrum of SCN2A mutations
Brain Dev
(2012) - et al.
Acute encephalopathy with a novel point mutation in the SCN2A gene
Epilepsy Res
(2012)
Cited by (19)
Clinical and genetic spectrum of SCN2A-associated episodic ataxia
2019, European Journal of Paediatric NeurologyCitation 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
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 DisabilityDe Novo Mutations of RERE Cause a Genetic Syndrome with Features that Overlap Those Associated with Proximal 1p36 Deletions
2016, American Journal of Human GeneticsCitation 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
Missense mutations in sodium channel SCN1A and SCN2A predispose children to encephalopathy with severe febrile seizures
2015, Epilepsy ResearchCitation 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.
Exploring the Spectrum of RHOBTB2 Variants Associated with Developmental Encephalopathy 64: A Case Series and Literature Review
2023, Movement Disorders Clinical Practice