SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet

SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet

Brain & Development 37 (2015) 729–732 Case Report SCN2A mutation in a Chinese boy with infantile spasm - response t...

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Brain & Development 37 (2015) 729–732

Case Report

SCN2A mutation in a Chinese boy with infantile spasm - response to Modified Atkins Diet Virginia C.N. Wong a,b,⇑, C.W. Fung a,b, Anna K.Y. Kwong b a

Division of Paediatric Neurology/Developmental Behavioural Paediatrics/NeuroHabilitation, Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, China b Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China Received 4 August 2014; received in revised form 25 September 2014; accepted 9 October 2014

Abstract Background: Mutation of SCN2A, encoding for voltage-gated sodium channel type II alpha subunit, has been demonstrated in various epilepsy phenotypes, ranging from benign to severe epileptic disorders and recently this had been reported for cases with infantile spasm (IS). Methods: We study a 6 years-old Chinese boy with severe developmental delay who had infantile spasm since 15 months. He later had severe intellectual disability and autistic features. He failed to respond to most anticonvulsants. Modified Atkins Diet was introduced at 4 years of age and he showed a seizure remission for 12 months with only 1 anticonvulsants. To clarify the unknown etiology, mutations were screened for genes associated with brain development or synaptic function. Results: A heterozygous mutation (c.3631G > A; p.E1211K) was identified in exon 21 of SCN2A gene. This mutation has been reported previously only in a Japanese patient with IS. Conclusion: This is the first case of SCN2A mutation identified in Chinese. Similarity of our case and one Japanese case of infantile spasm indicated that this E1211K mutation is important as possible etiology of IS. Trial of Modified Atkins Diet for other cases of infantile spasm with similar SCN2A mutations is worthwhile pursuing. Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Infantile spasm (IS); Epilepsy; Sodium channel; SCN2A; Modified Atkins Diet

1. Introduction Infantile spasm (IS) is catastrophic childhood epileptic syndrome. Although it is generally agreed that IS can be due to heterogeneous causes, including genetic, metabolic or structural conditions [1], the underlying ⇑ Corresponding author at: Rm 105 New Clinical Building, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Hong Kong Special Administrative Region. Tel.: +852 2255 4091, fax: +852 2255 1523. E-mail address: [email protected] (V.C.N. Wong).

pathological mechanism is not known and there is still no targeted treatment for this epileptic syndrome. Increasing evidence has shown that IS can be due to mutation of genes involved in the pathways for brain function and development [1,2]. Studies had identified the mutations of several epilepsy-associated genes such as SCN2A ARX, CDKL5 and STXBP1 in IS [3–6]. In the present study, mutations were screened for genes associated with brain development or synaptic functions (SCN1A, SCN2A, STXBP1, ARX, CDKL5, and KCNQ2) in a Chinese boy with IS and a recurrent SCN2A mutation was identified. 0387-7604/Ó 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.


V.C.N. Wong et al. / Brain & Development 37 (2015) 729–732

2. Case report This Chinese boy was the first child of non-consanguineous Chinese parents. There was no family history of convulsion, epilepsy or other neurological conditions. He had developmental delay since birth. He developed flexor spasm of his upper limbs occurring in clusters since 15 months. Physical examination showed no dysmorphic features, normal growth including the head circumference. He had developmental regression and autistic features later during subsequent follow up. Electroencephalography (EEG) showed modified hypsarrhythmia. He did not show any response to a trial of pyridoxine and folinic acid. His seizures were not responsive to multiple anticonvulsants including sodium valproate, clobazam, levetiracetam, vigabatrin or synthetic ACTH. Extensive neurometabolic investigations were performed were normal except mild cerebral folate deficiency with low 5-methyltetrahydrofolate 61 nmol/L (normal = 64–182). Folinic acid replacement did not show any clinical improvement. Magnetic resonance imaging and spectroscopy of the brain were normal. Modified Atkins Diet (MAD) was started at 4 years and currently, he was seizure free for 24 months and at the latest follow up, sodium valproate had been tailed off as well. Currently he is only on MAD without any anticonvulsants. His latest EEG showed generalized slowing of background without epileptic discharges. At the age of 6 years, this boy still had severe intellectual disability but he had marked improvement in his eye contact and social responsiveness and he started to walk unsupported for 20 steps with seizures in remission. All exons covering the coding regions as well as the splice junctions of SCN1A, SCN2A, STXBP1, ARX, CDKL5, and KCNQ2 genes of the patient DNA were amplified by polymerase chain reaction (PCR) and sequenced. Mutation analysis was performed by alignment with the reference genomic sequences and a

heterozygous mutation (c.3631G > A; p.E1211 K) in exon 21 of SCN2A gene was revealed (Fig. 1). The mutation was discriminated from single nucleotide polymorphisms (SNP) reported in NCBI SNP and Ensembl SNP database. Alignment of SCN2A orthologous and paralogous sequences demonstrated that this mutation affected highly conserved amino acid (Fig. 1) and the mutation was predicted to be deleterious to protein function and pathogenic by PolyPhen-2, SIFT and Align-GVGD analysis. This mutation has been reported previously in a patient with sporadic IS, marked developmental delay and severe intellectual disability [6]. Only mother’s DNA was available and no mutation was found in exon 21 of SCN2A gene for mother’s DNA. The father refused to have blood taken for genetic testing. 3. Discussion SCN2A is one of the candidate genes underlying the etiology of intractable infantile epilepsy. It encodes for voltage-gated sodium channel, type II, alpha subunit which is one of the members of sodium channel alpha subunit family for generation and propagation of action potentials in neurons and muscles [7]. SCN2A mutations had been reported to be associated with mild cases of epilepsy such as febrile seizures and benign familial neonatal-infantile seizures (BFNIS) [8]. From 2004, the clinical spectrum had expanded to other severe epileptic encephalopathies including IS, Dravet syndrome, Ohtahara syndrome, West syndrome and some unclassified early-onset epileptic encephalopathies [6,9–11]. Besides, other studies demonstrated that SCN2A mutations had been associated with intellectual disability or autism spectrum disorder with no history of seizure [12,13]. As of 2014 September, more than 70 cases of SCN2A mutations had been documented and the mutations resulted in a wide range of mild to severe neurodevelopmental disorders. Until now, there was no SCN2A mutation

Fig. 1. Heterozygous SCN2A mutation in the case with infantile spasm and ClustalW2 alignment of orthologous and paralogous SCN2A sequences showing that the affected amino acid residue is highly conserved.


Infantile spasm

15 Months

Severe developmental delay, severe intellectual disability; autistic features

– Severe developmental delay R853Q Japan



Sundaram [15] Nakamura [11] Wong 2013


12 Months K1422E

Infantile spasms (bitemporal glucose hypometabolism on PET scan) West syndrome

10 Months

Tonic seizures, clonic movements, status epilepticus – USA


Marked developmental delay; intellectual disability Autistic features 11 Months

Seizure onset Diagnosis

Infantile spasm E1211K Ogiwara [6] 2009


Clinical features Mutation Author




Table 1 Clinical features of patients with SCN2A mutations presenting as infantile spasms.

reported in Chinese in ethnic origin and we reported the first Chinese case. In the present study, the SCN2A mutation E1211K was located in a highly conserved region located in transmembrane segment 1 of domain III of the sodium channel alpha subunit. It was a recurrent mutation identified previously in a case with sporadic IS [6]. Ogiwara et al. [6] reported that E1211K mutation significantly changed the functional property of the sodium channels leading to both augmented and reduced channel activities by electrophysiological analyses. This mutation changed the channel properties to a greater extent than other mutations in some mild cases suggesting E1211K mutation is associated with the severe phenotypes [6]. Both the Japanese IS case and our Chinese case shared similar clinical features indicating that this mutation affected the neuron excitability of both in a similar way and this effect on the phenotypic expression was specific. However our case had autistic features as well. The patient failed to respond to trial of most anticonvulsants and had a markedly improved seizure control with MAD, at least as of the latest update of follow up for 12 months. MAD is a modified form of ketogenic diet. The ketogenic diet was showed to improve the seizure thresholds in mice with SCN1A mutation which is the major cause of Dravet syndrome [14]. Previous studies demonstrated a significant reduction of seizure frequency in patients with Dravet syndrome who were maintained on this diet [15,16]. Recent evidence showed that the ketones produced after MAD could reduce synaptic transmission and neuron excitability by inhibiting glutamate transport and activation of ATP-sensitive potassium channels [17]. These alterations may counteract with the change of neuron excitability caused by SCN2A mutation. SCN2A mutations in IS patients have been reported in other studies (Table 1). Sundaram et al. [18] reported a case of SCN2A mutation (K1422E) in IS associated with bitemporal hypometabolism. Nakamura et al. [11] identified SCN2A mutations in a case of West syndrome (R853Q) and several cases of Ohtahara syndrome evolving to West syndrome. These studies identified patients with similar phenotypes of IS but with mutations of SCN2A genes at different positions. The genotype-phenotype relationships is still unclear without further studies on how the positions of mutations affect channel function and neuron excitability. In conclusion, the present study identified the first SCN2A mutation in Chinese and this is a recurrent mutation reported previously. Similar clinical features of our patient to the Japanese case demonstrated that this particular E1211K mutation is important for IS pathophysiology. The good response of seizures to MAD is worth exploring for other IS cases with SCN2A mutations.

Other seizure types

V.C.N. Wong et al. / Brain & Development 37 (2015) 729–732


V.C.N. Wong et al. / Brain & Development 37 (2015) 729–732

Acknowledgments We would like to acknowledge the Society for the Relief of Disabled Children for donations for the genetic study. This research is supported by the project funding of University Research Committee, The University of Hong Kong. Ethical approval had been obtained from the Institutional Review Board (IRB) of the University of Hong Kong-Hong Kong West Cluster. References [1] Paciorkowski AR, Thio LL, Dobyns WB. Genetic and biologic classification of infantile spasms. Pediatr Neurol 2011;45:355–67. [2] Mastrangelo M, Leuzzi V. Genes of early-onset epileptic encephalopathies: from genotype to phenotype. Pediatr Neurol 2012;46:24–31. [3] Stromme P, Mangelsdorf ME, Scheffer IE, Gecz J. Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain Dev 2002;24:266–8. [4] Weaving LS, Christodoulou J, Williamson SL, Friend KL, McKenzie OL, Archer H, et al. Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation. Am J Hum Genet 2004;75:1079–93. [5] Mignot C, Moutard ML, Trouillard O, Gourfinkel-An I, Jacquette A, Arveiler B, et al. STXBP1-related encephalopathy presenting as infantile spasms and generalized tremor in three patients. Epilepsia 2011;52:1820–7. [6] Ogiwara I, Ito K, Sawaishi Y, Osaka H, Mazaki E, Inoue I, et al. De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. Neurology 2009;73:1046–53. [7] Yu FH, Catterall WA. Overview of the voltage-gated sodium channel family. Genome Biol 2003;4:207.

[8] 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. [9] Shi X, Yasumoto S, Nakagawa E, Fukasawa T, Uchiya S, Hirose S. Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. Brain Dev 2009;31:758–62. [10] Kamiya K, Kaneda M, Sugawara T, Mazaki E, Okamura N, Montal M, et al. A nonsense mutation of the sodium channel gene SCN2A in a patient with intractable epilepsy and mental decline. J Neurosci 2004;24:2690–8. [11] Nakamura K, Kato M, Osaka H, Yamashita S, Nakagawa E, Haginoya K, et al. Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. Neurology 2013;81:992–8. [12] Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012;380:1674–82. [13] Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by wholeexome sequencing are strongly associated with autism. Nature 2012;485:237–41. [14] Dutton SBB, Sawyer NT, Kalume F, Jumbo-Lucioni P, Borges K, Catterall WA, et al. Protective effect of the ketogenic diet in Scn1a mutant mice. Epilepsia 2011;52:2050–6. [15] Dressler A, Stocklin B, Reithofer E, Benninger F, Freilinger M, Hauser E, et al. Long-term outcome and tolerability of the ketogenic diet in drug-resistant childhood epilepsy – The Austrian experience. Seizure 2010;19:404–8. [16] Nabbout R, Copioli C, Chipaux M, Chemaly N, Desguerre I, Dulac O, et al. Ketogenic diet also benefits Dravet syndrome patients receiving stiripentol: a prospective pilot study. Epilepsia 2011;52:54–7. [17] Lutas A, Yellen G. The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci 2013;36: 32–40. [18] Sundaram SK, Chugani HT, Tiwari VN, Huq AHMM. SCN2A mutation is associated with infantile spasms and bitemporal glucose hypometabolism. Pediatr Neurol 2013;49:46–9.