Case Series of Early SCN1A-Related Developmental and Epileptic Encephalopathies.

Introduction: The developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of rare neurodevelopmental disorders, characterized by early onset seizures that are often intractable, electroencephalographic abnormalities, developmental delay, or regression. The SCN1A pathogenic variants can present as DEE. They are characterized by early infantile seizure onset, profound intellectual disability, and a severe hyperkinetic movement disorder. Studies are lacking, hence we are reporting a case series of early SCN1A-related DEE. The objective of the study was to report clinical and molecular aspects of early SCN1A-related DEE. Materials and
Methods: A retrospective chart review of children with DEEs secondary to SCN1A pathogenic variants from January 2015 to March 2020 in a tertiary care referral center from south India.
Results: Out of eleven children, seven were boys. The mean age of presentation was 3.5 months. Nine children had seizures triggered by fever. All the children presented with focal and generalized seizures along with epileptic spasms. No focal neurological deficits were noted; routine testing, neuroimaging, and metabolic tests were normal in all the cases. In all the cases, hypsarrhythmia was noted on electroencephalogram (EEG). All the children had pathogenic variants in the SCN1A gene. Five children responded to steroids, one child responded to vigabatrin, and one child responded to stiripentol, but all of them had relapsed and were refractory to other antiepileptic drugs. At follow-up, all children had developmental delays and six of them had autistic features.
Conclusion: Early SCN1A-related encephalopathies should be considered in the differential diagnosis of early infantile epileptic encephalopathies. Identification of this condition is important, as treatment and outcome are different from other epileptic encephalopathies. Copyright:

INTRODUCTION

The DEEs are a heterogeneous group of rare epilepsy syndromes, characterized by early onset seizures that are often intractable, developmental delay or regression, electroencephalographic abnormalities that can directly worsen cognition and behavior, in some cases early death.[1] These syndromes involve impaired development (developmental encephalopathies) and regression of developmental progress (epileptic encephalopathies). Various genes known to be associated with DEEs are mutations in SCN2A, KCNQ2, SCN1A, STXBP1, CDKL5, MECP2, CACNA1A, GRIN1, SCN1B, and PCDH19.[2]

The SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures to DEEs.[3] The SCN1A-related DEE is distinctive that is far more severe than Dravet syndrome (DS). It is characterized by early infantile seizure onset, profound intellectual disability, and a severe hyperkinetic movement disorder.[4] There are a lack of studies on SCN1A-associated DEE; hence, we are reporting 11 children who presented with epileptic encephalopathy secondary to early SCN1A DEE.

MATERIALS AND METHODS

This is a retrospective chart review of children with early SCN1A-related DEEs from the tertiary care referral center, from the southern part of India. The medical records of children attending the pediatric neurology clinic and those who were admitted to the pediatric neurology and pediatric ward from January 2015 to March 2020 were analyzed. Among them, only children who were confirmed to have the SCN1A gene mutation in genetic studies and presented with epileptic encephalopathy were included. Those children with suspected epileptic encephalopathy without genetic confirmation were excluded. The data were extracted in a predesigned proforma. Details of history, including birth history, developmental history, clinical features including seizure semiology, precipitation of seizures with fever, investigations such as complete hemogram, liver function, renal function, serum calcium, serum ammonia, serum lactate, arterial blood gas, and MRI of the brain, were taken. Special investigations such as tandem mass spectrometry (TMS), EEG, and genetic analysis were also taken. Statistical analysis was performed with SPSS version 21. The results were analyzed. Ethical clearance was obtained from the institutional ethical committee.

RESULTS

A total of 605 children with epileptic spasms and 50 children with Dravet syndrome were noted during this study period. Of the 31 children with the SCN1A gene mutation, 11 out of 31(35%) had early onset epileptic encephalopathies. The various clinical features, laboratory findings, and outcomes of all the 11 children are mentioned in Table 1. Of the 11 children, seven (64%) were boys. All of them presented in early infancy, with the mean age of presentation being 3.5 months of age. All of them presented with pleomorphic seizures in the form of focal or generalized seizures along with epileptic spasms. Nine children (82%) presented with fever-triggered seizures, and two children (18%) presented with seizures after vaccination. Birth history, metabolic testing including tandem mass spectrometry, and MRI of the brain, were normal in all the children. EEG showed hypsarrhythmia in all the children. The EEG in Figures 1 and 2 shows hypsarrhythmia. Targeted next-generation sequencing indicating various mutations in the SCN1A gene in all the children is shown in Table 2. Sanger sequencing in parents of all children was negative, which was suggestive of de novo mutations. Spasms were controlled with steroids in five children (45%); one child (9%) responded to vigabatrin; and five children were given a stiripentol, among whom one child (9%) responded. At follow-up, all of them had relapsed and were refractory to other antiepileptic drugs. The development of all the children was delayed, and six children (54%) developed autistic features.

Table 1

Showing various clinical and laboratory profile of SCN1A-related DEEs

Case No.	Sex	Age of onset (m.)	Fever triggered seizures	Seizure type	Clinical features	Last follow-up (mo.) and Dev	AED tried	Response to AED
1.	M	3	No	GTCS, ES	GDD	45, NA	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	VB
2.	M	3	Yes	Focal, ES	GDD Autistic	42, NA	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	ACTH
3.	M	3	No	GTCS, F, ES	GDD	60, NA	VPA, SP, LEV,CZM, TPM,ZSM, VB,ACTH	None
4.	F	2	Yes	GTCS, F, ES	GDD Autistic	13, NA	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	ACTH
5.	F	3	Yes	GTCS, F, ES	GDD Autistic	48, NA	VPA, SP, LEV,CZM, TPM,ZSM, VB,ACTH	None
6.	M	3	Yes	GTCS, F, ES	GDD	12 , Autistic	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	ACTH
7.	M	3	Yes	GTCS, F, ES	GDD Autistic	28, Amb Autistic	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	ACTH
8.	M	5	Yes	GTCS, F, ES	GDD Autistic	25,NA Autistic	VPA, SP, LEV,CZM, TPM,ZSM, VB,ACTH	SP
9.	F	1	Yes	GTCS, F, ES	GDD	12, NA Autistic	VPA, SP, LEV,CZM, TPM,ZSM, VB,ACTH	None
10.	F	7	Yes	GTCS, F, ES	GDD	21, Amb, Autistic	VPA, LEV,CZM, TPM,ZSM, VB,ACTH	ACTH
11.	M	6	Yes	GTCS, F, ES	GDD Autistic	24, NA Autistic	VPA, SP, LEV,CZM, TPM,ZSM, VB,ACTH	None

ACTH: Adrenocorticotropic hormone, AEDs: Antiepileptic drugs, Amb: Ambulatory, CLB: Clobazam, CBZ: Carbamazepine, DEV: Development, ES: Epileptic Spasms, F: Focal, GDD: Global developmental delay, GTCS: Generalized tonic-clonic seizures, LEV: Levetiracetam, NA-Non ambulatory, SP: Stiripentol, VPA: Valproate, TPM; Topiramate, VB: Vigabatrin, ZNS: Zonisamide

Figure 1

EEG of bipolar longitudinal montage with a sensitivity of 20 microvolts showing high-amplitude multifocal spikes, sharp waves with secondary generalization followed by suppression suggestive of modified hypsarrhythmia in a 5-month-old child with DEE due to SCN1A pathogenic variant

Figure 2

EEG with a sensitivity of 50 µV showing high-amplitude multifocal spikes, sharp waves with chaotic background activity suggestive of hypsarrhythmia

Table 2

Showing various pathogenic variants in SCN1A-related DEEs

Case	Exon	Variant	Zygosity	ACMG Classification
1.	16	NM_006920.6 c.3199G>A (p.Asp1067Asn)	Het	VUS
2.	8	NM_006920.6 c.3199G>A (p.Ala1067Thr)	Het	P
3.	15	NM_006920.6 c.2712dupT (p.Ala905CysfsTer10)	Het	P
4.	26	NM_001202435.3 c.4855A>G (p.Met1619Val)	Het	VUS
5.	26	NM_001353955.2 c.4907G>A (p.Arg1636His)	Het	LP
6.	16	NM_001353948.2 c.5030T>C (p.Leu1677Pro)	Het	VUS
7.	6	NM_006920.6 c.695G>T (p.Gly232Val)	Het	P
8.	2	NM_001165963.3 c.316_319delTCTGinsC (p.Ser106_Ala107delinsPro)	Het	VUS
9.	14	NM_006920.6 c.2505 + 3A>T	Het	P
10.	11	NM_006920.6 c.695G>T (p.Gly232Val)	Het	P
11.	8	NM_006920.6 c.5734C>T (p.Gln1912Ter)	Het	LP

Het = heterozygous; LK = likely pathogenic; P = pathogenic; VUS = variant of uncertain significance

DISCUSSION

The SCN1A disorders represent the archetypal channelopathy associated with epilepsy. More than 1200 variants associated with epilepsy have been reported in SCN1A.[5] Truncating variants are almost always associated with severe phenotypes and cause loss of function, proving that haploinsufficiency of SCN1A is pathogenic, whereas missense variants are associated with milder forms of epilepsy.[6] They result in a wide phenotypic spectrum ranging from self-limited and pharmaco-responsive epilepsies, such as genetic epilepsy with febrile seizures plus (GEFS+), to DEEs. Even within the DEEs, there is a spectrum of severity ranging from myoclonic-atonic epilepsy (MAE) to DS, epilepsy of infancy with migrating focal seizures (EIMFS), and early onset SCN1A DEE.[3] Each has a different range of comorbidities and prognosis, which is determined by different functional deficits. A few reports describe early epileptic encephalopathy secondary to a mutation in the SCN1A gene in the literature. Here, we are reporting 11 patients presenting with early DEE secondary to a mutation in the SCN1A gene.

Early infantile SCN1A encephalopathy can be readily distinguished from Dravet syndrome by several features. It has a younger age at onset, beginning at three months compared with the typical seizure onset age range of 4 to 15 months in Dravet syndrome. The mean age of onset in our series is 3.5 months. It is associated with profound developmental impairment rather than the severe-to-mild intellectual disability usually seen in Dravet syndrome.[4] All cases in this study had severe developmental delays, including autistic features. Other features differentiating early infantile SCN1A encephalopathy from Dravet syndrome are epileptic spasms, which are not seen commonly in Dravet syndrome. Epileptic spasms were noted in all our cases.

The etiology of epileptic spasms is widely heterogeneous, with acquired and congenital causes. Significant advances have been obtained these past few years, especially with regards to genetic investigations. More than 10 genes were associated with epileptic spasms.[7] More recently, copy-number variations (CNVs) and mutations in STXBP1, SCN2A, and KCNQ2, which were previously associated with early onset epileptic encephalopathy, have been found in patients with epileptic spasms.[8] Despite these advances, in many cases, the cause remained hidden.[9] Wallace et al. extend the phenotypic heterogeneity of mutations in SCN1A to include epileptic spasms.[10] In our study, SCN1A mutations are responsible for 11 out of 605(1.8%) of epileptic spasms during the study period.

In two children, initial seizures were noticed after DPT vaccine and they subsequently developed epileptic spasms. This finding was consistent with other studies of seizures after vaccinations that were reported in 7–57% of children with SCN1A-related DEE.[1112] Ogiwara et al.[13] reported a mutation in SCN2A-E1211K, causing epileptic spasms. Nakamura et al.[14] reported nine of 67 Ohtahara syndrome (OS) cases (13.4%), and one of 150 West syndrome cases (0.67%) were secondary to the SCN2A mutation. All nine mutations in patients with OS were in linker regions between two transmembrane segments. In seven of the nine patients with OS, EEG findings transitioned from suppression-burst pattern to hypsarrhythmia.

Harkin et al.[15] described the missense SCN1A variant; Nav1.1-p.Thr226Met (T226M) is associated with a far more profound clinical phenotype than typical DS, and it represents a new class of early infantile epileptic encephalopathy (EIEE) located even beyond DS on the classical severity spectrum of SCN1A-linked disorder. Sadleir et al.[4] described the clinical presentation of more severe SCN1A-linked “early infantile SCN1A encephalopathy.” This group identified eight unrelated patients with an identical, presumed de novo missense mutation resulting from c.677C>T in SCN1A exon 5. A ninth unrelated patient, with the de novo SCN1A missense mutation p.Pro1345Ser (c.4033C>T), was also included in the study due to the similarities in symptomology to the T226M patients—thus illustrating that early infantile SCN1A encephalopathy can arise from more than one particular variant. In our study, all of them showed pathogenic or likely pathogenic variants in the SCN1A gene, except in four cases where it was suggestive of a variant of uncertain significance (VUS). In these four cases, clinical features, laboratory findings are consistent with SCN1A DEE; hence, they are clinically considered as significant. The strongest evidence for pathogenicity in an affected child with a VUS would be absence of mutations in unaffected parents. None of our cases had the T226M variant as described by Sadleir et al. We are reporting three novel mutations, NM_006920.6 c.2712dupT (p.Ala905CysfsTer10), NM_006920.6 c.695G>T (p.Gly232Val), and NM_001165963.3 c.316_319delTCTGinsC (p.Ser106_Ala107delinsPro).

The mean age of presentation is our study was 3.5 months, similar to the mean age of presentation being three months for the A1057T variant. Males are most affected. Six of them (54%) had autistic features. Epilepsy is refractory in all children; however, epileptic spasms responded to steroids in five children and to vigabatrin in one child but later relapsed and became refractory requiring polytherapy. Five children received Stiripentol; among them, only one child had a partial response with a 75% reduction in seizures.

In addition, early infantile SCN1A encephalopathy presents with hyperkinetic movements, appearing as early as nine weeks of age, including choreoathetosis, dystonia, myoclonus, and perioral hyperkinesia. Although hyperkinetic movements are not characteristic of SCN1A-linked DS, similar movement disorders are associated with SCN2A and SCN8A-linked EIEEs; this overlap in symptomology led Sadleir et al. to speculate that the early infantile SCN1A encephalopathy, such as SCN2A- and SCN8A-linked EIEEs, may be associated with a gain-of-function (GOF) variant. In contrast to this, none of the children in our study showed hyperkinetic movements.

Epileptic spasms can be the presenting feature in early SCN1A-related DEE. They present earlier than classical Dravet syndrome with more severe developmental delay and refractory to treatment. Larger studies are required to correlate phenotype and genotype correlations of SCN1A-related DEE, as our genotype and phenotype is different from Sadlier et al.

CONCLUSION

In all cases of unexplained epileptic spasms and DEE, one should consider the possibility of the SCN1A gene mutation and genetic testing should be considered. Early identifications are useful to select antiepileptic drugs for this subgroup of epileptic spasms.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.