Brain & Development xxx (2014) xxx–xxx www.elsevier.com/locate/braindev

Case Report

A case of recurrent encephalopathy with SCN2A missense mutation Tatsuya Fukasawa a,⇑, Tetsuo Kubota a, Tamiko Negoro a, Makiko Saitoh b, Masashi Mizuguchi b, Yukiko Ihara c, Atsushi Ishii c, Shinichi Hirose c b

a Department of Pediatrics, Anjo Kosei Hospital, Aichi, Japan Department of Developmental Medical Sciences, Graduate School of Medicine, University of Tokyo, Japan c Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan

Received 22 July 2014; received in revised form 29 September 2014; accepted 1 October 2014

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 Nav1.2, 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. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: SCN2A; Mutation; Encephalopathy

1. 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 ⇑ Corresponding author at: Department of Pediatrics, Anjo Kosei Hospital, 28 Higashihirokute Anjo-cho, Anjo-shi, Aichi-pref 446-8602, Japan. Tel.: +81 566 75 2111; fax: +81 566 76 4335. E-mail address: [email protected] (T. Fukasawa).

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.

http://dx.doi.org/10.1016/j.braindev.2014.10.001 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Fukasawa T et al. A case of recurrent encephalopathy with SCN2A missense mutation.. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.001

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2. 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, diffusionweighted imaging (DWI) revealed high intensity areas (HIAs) in the diffuse subcortical white matter, bilateral thalami, and basal nuclei (Fig. 1). Examination of the cerebrospinal fluid (CSF) and blood showed no abnormalities. His symptoms improved gradually without any specific treatment. After this episode, a head magnetic resonance imaging (MRI) scan showed diffuse cerebral atrophy, and the patient exhibited motor milestone delay.

At the age of 10 months, he presented with fever, nasal congestion, and cough. Analysis of a sample taken from a nasopharyngeal swab for rapid respiratory syncytial virus using an antigen-detection assay was positive. The next day he developed nystagmus and disturbed consciousness. DWI revealed the presence of HIAs in the bilateral cerebellar hemispheres (Fig. 1). He received high-dose intravenous gammaglobulin and methylprednisolone pulse therapy, which gradually improved his symptoms. A head MRI showed cerebellar atrophy, but his electroencephalogram (EEG) showed no abnormal findings, and he had no seizures or obvious sequelae after this episode. At the age of 14 months, he suffered an episode of fever, vomiting, and diarrhea, with repeated generalized tonic-clonic convulsions the same day. Examination of his CSF was normal. DWI revealed HIAs in the diffuse right hemisphere and left frontal lobe. He received highdose intravenous gammaglobulin and methylprednisolone pulse therapy. However, 2 days later, DWI revealed the presence of diffuse HIAs in the bilateral hemisphere, except for in the bilateral thalami. After this episode, a head MRI showed severe cerebral atrophy, and his interictal EEG showed frequent spikes and sharp waves in the right fronto-temporal regions. He had severe neurological sequelae and spastic quadriplegia; he became bedridden and required tube feeding, and tonic seizures occurred several times a day. Genetic analysis of 26 exons of the SCN2A gene using PCR revealed a missense mutation c.4979T>G (p.Leu1660Trp), located between segment 4 and 5 of domain IV (Fig. 2). Amino acid residue of 1660 leucine is well conserved in other sodium channels, as well as other species. Sorting Intolerant From Tolerant (SIFT) predicted that this mutation may be highly damaging to the structure of Nav1.2. The score of SIFT was 0.00 (damaging) with Median Information of Content 3.39. This mutation has not been reported previously in the literature and was not detected in 80 normal individuals. Neither of his parents carried this mutation. 3. Discussion

Fig. 1. Head magnetic resonance imaging (MRI) of the patient. (A) At the age of 5 days, diffusion-weighted imaging (DWI) revealed highintensity areas (HIAs) in the subcortical white matter, bilateral thalami, and basal nuclei. T1-weighted imaging (T1WI) and T2weighted imaging (T2WI) showed no obvious abnormal findings. (B) At the age of 10 months, DWI revealed HIAs in the bilateral cerebellar hemispheres but not in the cerebral hemispheres. T1WI and T2WI showed no obvious abnormal findings. (C) At the age of 14 months, DWI showed diffuse HIAs in the right hemisphere and left frontal lobe at the time of symptom onset. (D) Two days later, the diffuse HIAs had enlarged into the bilateral hemisphere, excluding the thalami. T1WI and T2WI revealed a blurred cortical-white matter junction and diffuse cerebral edema.

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 a2-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 childhood epilepsies [6], and acute encephalitis with refractory, repetitive, partial seizures [7]. Considering the diverse effects of SCN2A mutations on sodium

Please cite this article in press as: Fukasawa T et al. A case of recurrent encephalopathy with SCN2A missense mutation.. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.001

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Fig. 2. Structure of human SCN2A with localization of a novel missense mutation, c.4979T>G (p.Leu1660Trp) (closed circle) in the linker between segment 4 and 5 of domain IV (a). Electropherogram of the patient’s mutation (b). Leu1660Trp mutation, affecting conserved amino acid in the SCN2A Leu1660 (boxed) and the surrounding amino acids are highly conserved in other sodium channels and vertebrate (c).

channels and the clinical course of our patient, we propose that some mutations in the SCN2A gene could cause repetitive encephalopathy. Second, SCN2A mutations may cause neonatal encephalopathy. Neonatal encephalopathy is caused by various etiologies, such as perinatal asphyxia, infections, and metabolic disorders. Although newborns with symptoms indicative of encephalopathy are examined for these etiologies, clear results are not always obtained. As such, the possibility that SCN2A mutations cause neonatal encephalopathy should be considered in the treatment of neonates with encephalopathy of unknown etiology. In this patient, different lesions were involved in each episode. Liao et al. reported that immunohistochemical and RT-PCR investigations revealed transiently higher expression of Nav1.2 channels in the axon initial segments of principal neurons during development [8]. Such findings may be associated with the differences in lesions according to age, in addition, variety of lesions may be characteristic of encephalopathy caused by SCN2A mutations. Voltage-gated sodium channels may play a role in disorders of excitability [9]. Mutations in SCN1A may cause specific physiological dysfunction in GABAergic neurons and alter the function of inhibitory circuits and contribute to epileptic seizures [10]. Mutations in SCN2A may cause acute encephalopathy by similar mechanisms.

Physicians should be aware that SCN2A mutations may cause repetitive encephalopathy during neonatal period and infancy.

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 on Innovative Areas (221S0002 and 25129708 to A.I and S.H.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), MEXT-supported Program for the Strategic Research Foundation at Private Universities 2013-2017 (S.H.), a Grant-in-aid for the Research on Measures for Intractable Diseases (No. H26-Nanji-Ippan-49 and 51 to S.H.) from the Ministry of Health, Labor and Welfare, Intramural Research Grant (24-7) for Neurological and Psychiatric Disorders of NCNP (S.H.), the Joint Usage/Research Program of Medical Research Institute, Tokyo Medical and Dental University (S.H.), Grants from The Mitsubishi Foundation (S.H.) and Takeda

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Scientific Foundation (S.H.), Grants from the Kobayashi Magobei Foundation (A.I.), the Japan Epilepsy Research Foundation Grant (to A.I.) and Kiyokun Foundation (S.H.). References [1] Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, 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;84:44–51. [2] Hidaka F, Matsuo S, Muta T, Takeshige K, Mizukami T, Nunoi H. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol 2006;119:188–94. [3] Saitoh M, Shinohara M, Hoshino H, Kubota M, Amemiya K, Takanashi J, et al. Mutations of the SCN1A gene in acute encephalopathy. Epilepsia 2012;53:558–64.

[4] Kubota M, Chida J, Hoshino H, Ozawa H, Koide A, Kashii H, 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;34:20–7. [5] Shinohara M, Saitoh M, Nishizawa D, Ikeda K, Hirose S, Takanashi J, et al. ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus. Neurology 2013;80:1571–6. [6] Shi X, Yasumoto S, Kurahashi H, Nakagawa E, Fukasawa T, Uchiya S, et al. Clinical spectrum of SCN2A mutations. Brain Dev 2012;34:541–5. [7] Kobayashi K, Ohzono H, Shinohara M, Saitoh M, Ohmori I, Ohtsuka Y, et al. Acute encephalopathy with a novel point mutation in the SCN2A gene. Epilepsy Res 2012;102:109–12. [8] Liao Y, Deprez L, Maljevic S, Pitsch J, Claes L, Hristova D, et al. Molecular correlates of age-dependent seizures in an inherited neonatal-infantile epilepsy. Brain 2010;133:1403–14. [9] Lossin C. A catalog of SCN1A variants. Brain Dev 2009;31:114–30. [10] Yamakawa K. Molecular basis of severe myoclonic epilepsy in infancy. Brain Dev 2009;31:401–4.

Please cite this article in press as: Fukasawa T et al. A case of recurrent encephalopathy with SCN2A missense mutation.. Brain Dev (2014), http://dx.doi.org/10.1016/j.braindev.2014.10.001

A case of recurrent encephalopathy with SCN2A missense mutation.

Voltage-gated sodium channels regulate neuronal excitability, as well as survival and the patterning of neuronal connectivity during development. Muta...
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