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LETTERS TO EDITOR
Year : 2019  |  Volume : 67  |  Issue : 1  |  Page : 264-267

Novel genotype–electroclinical phenotype correlations in sporadic early-onset childhood myoclonic–atonic epilepsy


1 R Madhavan Nayar Centre for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
2 Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Ponekkara, Kochi, Kerala, India

Date of Web Publication7-Mar-2019

Correspondence Address:
Dr. Ramshekhar N Menon
R Madhavan Nayar Centre for Comprehensive Epilepsy Care, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram - 695 011, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.253628

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How to cite this article:
Babu SP, Menon RN, Asranna A, Nampoothiri S, Radhakrishnan A, Cherian A, Thomas SV. Novel genotype–electroclinical phenotype correlations in sporadic early-onset childhood myoclonic–atonic epilepsy. Neurol India 2019;67:264-7

How to cite this URL:
Babu SP, Menon RN, Asranna A, Nampoothiri S, Radhakrishnan A, Cherian A, Thomas SV. Novel genotype–electroclinical phenotype correlations in sporadic early-onset childhood myoclonic–atonic epilepsy. Neurol India [serial online] 2019 [cited 2019 Mar 18];67:264-7. Available from: http://www.neurologyindia.com/text.asp?2019/67/1/264/253628




Sir,

We would like to report two cases of myoclonic–atonic epilepsy (MAE).

A 7-year old boy, born of a nonconsanguineous parentage presented with recurrent seizures. There was no prior perinatal insult or developmental delay. At 5 years of age, his parents noticed sudden appendicular myoclonic jerks. These jerks increased in severity and frequency over the next 6 months into episodes associated with sudden head drops. By this time, episodes of absences often lasting for 1–2 minutes associated with eye blinks were noted. At the age of 6 years, recurrent falls were noted associated with proximal upper limb myoclonic jerks. No significant improvement in these spells was noted on a combination of valproic acid, levetiracetam, and clonazepam/clobazam. No cognitive decline, family history of epilepsy, or other neurological illnesses were noted. The neurological examination was unremarkable and his development quotient was age appropriate. Magnetic resonance imaging (MRI) of the brain was normal. His interictal and ictal video-electroencephalography (EEG) was consistent with an atypical form of MAE with associated atypical absences with frontal dominant generalized discharges, frontocentral theta activity and documented negative myoclonus corresponding to the slow wave phase of the generalized discharges, as demonstrated in [Figure 1]. His fasting cerebrospinal (CSF) study revealed no hypoglychorrachia, and his skin biopsy as well as median somatosensory evoked potentials were normal. Targeted next-generation sequencing was ordered, which covered the epilepsy-related genes, as detailed in Appendix 1. This revealed a heterozygous missense variation in exon 2 of the SCN2A gene (chromosome [chr] 2: 166152403 G>G/A; p. Ala24Thr). On a combination of zonisamide, valproic acid, and clonazepam, he is currently seizure free with mild scholastic issues.
Figure 1: EEG of the patient 1:(a) Multiple episodes of atonic drops and (b) atypical absences were recorded; ictal correlate of the myoclonic phase was a repetitive burst of frontal dominant generalized spike and wave discharges; the drop/atonic phase corresponded to the slow wave component of the generalized discharges as indicated by the vertical marker. (c) Inter-ictal data: Frontal dominant generalized discharges with fronto-central theta-delta range slow waves with a background activity of 8–8.5Hz with continued activation during sleep (d)

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A 6-year old boy, born of nonconsanguineous parentage with antecedent intrauterine growth retardation and no significant family history, presented with recurrent seizures. His birth weight was 2.25kg. Moderate developmental delay was noted. From 15 months of age, he had typical febrile generalized tonic–clonic seizures (GTCs). At 3 years of age, he developed recurrent head drops without associated tonic seizures, proximal, or distal limb myoclonus, with upto 50 episodes per day, following which he was noted to have transient regression in language and socio-adaptive cognitive spheres. On presentation, he had a developmental age of 3 years and was on a combination of sodium valproate, lacosamide, and clobazam. He was suffering from recurrent atonic drop attacks and rare nocturnal GTCs with no lateralizing features. His general examination revealed microcephaly with no dysmorphic features and subtle multifocal myoclonus without any overt ataxia or focal deficits. His interictal and ictal video-EEG was consistent with symptomatic myoclonic epilepsy with frontal and occipital dominant generalized interictal epileptiform discharges (IEDs) and documented myoclonus corresponding with generalized discharges followed by the atonic neck drop during the slow wave of the generalized discharge, as shown in [Figure 2]. Although the recorded events were consistent with myoclonic–atonic seizures, the developmental status, microcephaly, and florid multifocal myoclonus favored a syndromic diagnosis of myoclonic epilepsy secondary to a structural/metabolic cause including gliosis, mitochondrial disorders, and Dravet syndrome (DS) in view of the prior febrile seizures. His MRI brain and CSF examination were normal. Median nerve somatosensory evoked potentials were normal and skin biopsy with electron microscopy did not reveal intracytoplasmic/nuclear inclusions, thereby excluding the progressive myoclonus epilepsy (PME) syndromes. His drop attacks ceased on a combination of lamotrigine and sodium valproate; however, he was noted to develop action myoclonus and mild worsening of ataxia with no developmental regression. Considering this exacerbation of myoclonus on lamotrigine, he was optimized on a combination of zonisamide and valproate, with disappearance of myoclonus and atonic drop attacks. Targeted genetic testing revealed a heterozygous variant in exon 12 of the SCN5A gene (chr3:38645535T>C; c.558A>G; p. Met520Val).
Figure 2: Ictal correlate of myoclonic-atonic seizures in patient 2: (a) Generalized spike-polyspike and wave discharge associated with myoclonus followed by truncal atonia noted during the slow wave phase. (b) Posterior dominant 7–8Hz rhythm with intermixed occipital slow waves with burst of occipital dominant generalized spike and wave discharges. No correlate for multifocal myoclonus noted. (c) Drowsy record showing fragmented low-amplitude occipital spikes. P3 artifact was also noted

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Across all idiopathic myoclonic epilepsy syndromes, hereditary transmission may be autosomal, recessive or dominant or may be more complex with locus heterogeneity.[1] Specific gene mutations have been found in sodium-channel components in our series. In this series, we utilized targeted next-generation sequencing which represents a cost-effective approach to detect variants present in multiple/large genes in an individual. Selective capture and sequencing of the protein coding regions of the genome/genes is performed in this technique.[2] The absence of family history in both probands favored the fact that the identified mutations were likely to be de-novo mutations, as is well known with SCN1A mutations in DS.[3] The identified mutations may, however, represent variants of unknown significance, and in such situations, one needs to perform parental gene studies. If either of the parents has the mutation, it may be considered a significant polymorphism. To call this change as the causative one, functional studies need to be done. In our patients, we can neither commit on the causality nor recommend prenatal studies to the families. We have hypothesized the significance of these channelopathies in producing the phenotypes described; thus, even minor changes in channel activity might have been functionally significant in the diseased state and might have acted synergistically with other factors to contribute to generalized epileptic myoclonus with other seizure types such as atonic seizures and atypical absences.

The electroclinical phenotype of the first case was indicative of MAE. During the last few years, several mutations in SCN1A, SCN1B, GABRG2, and SLC2A1 genes have been reported in isolated cases of MAE. In a study which sequenced 644 individuals with epileptic encephalopathies, six SLC6A1 mutations were identified in seven individuals, all of whom had MAE.[4] However, these pathogenic mutations accounted only for ~4% of cases, thus highlighting the genetic heterogeneity. In the first proband, we identified variations in the SCNA2 gene. The SCN2A gene encodes the voltage-gated sodium channel Nav1.2, one of the major neuronal sodium channels that play a role in the initiation and conduction of action potentials. Nav1.2 is expressed in the initial segments of the axon and nodes of Ranvier of myelinated nerve fibres in early development, and in the adult brain in the initial segment of the axon and unmyelinated axons.[5],[6] The phenotype reported with missense mutations in this gene includes the early infantile epilepsy with onset before 3 months of age. This occurs due to gain-of-function effects with correlation with the severity of the clinical phenotype and a relatively good response to drugs acting via the sodium channel blockade (SCB).[7] Another subgroup is characterized by epilepsy onset after 3 months of age due to loss-of-function mutations/effects and a relatively poor response to SCBs. The phenotypes in the early-onset group comprise benign neonatal seizures, Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and unclassified developmental encephalopathies; whereas, the late onset cases include West syndrome, Lennox–Gastaut syndrome, MAE, and focal epilepsies with electrical status epilepticus in sleep. Our case fits into the latter subgroup.

Mutations in the SCN5A gene reported in patient 2 are reportedly cardiac channelopathies associated with Brugada syndrome and the congenital long-QT-syndrome (LQTS) type 3, as it codes for cardiac sodium channel, voltage gated, type V, alpha subunit.[8] In addition to sudden cardiac death, such mutations may cause syncope and seizures. There is no convincing clinical evidence that mutations in the SCN5A gene may cause isolated epilepsy. However, the SCN5A gene has been shown to be selectively expressed in the limbic regions of rat brain and it is suggested by some authors that SCN5A mutations may be expressed in some forms of primary inherited epilepsy.[9] With the electroclinical phenotype mimicking symptomatic myoclonic epilepsy, and the paradoxical aggravation of myoclonus with a specific SCB such as lamotrigine (similar to what has been reported with SCN1A phenotypes such as DS, and genetic generalized epilepsies such as juvenile myoclonic epilepsy [JME]), this novel SCN5A mutation may support the notion that an ion channel mutation may be expressed in the brain and give rise to a susceptibility for epileptic seizures with the specific phenotype being reported. The electrocardiogram (ECG) and Holter monitoring in our case were normal. Considering the recent report of this mutation in an adult with JME who subsequently developed LQTS3, a close cardiology follow-up is warranted in our case.[10] However, whether this mutation implies causation requires further consistency of observations in similar probands. In 4 affected members of a family with idiopathic generalized epilepsy (see 611942), Heron et al., (2007) identified a heterozygous variant in the CACNA1H gene, resulting in an ala876-to-thr (A876T) substitution in a conserved residue in domain II S3 region of the protein. The specific phenotypes were variable and included childhood absence epilepsy, febrile seizures, temporal lobe epilepsy, and generalized epilepsy. In vitro functional expression studies demonstrated that the A876T variant resulted in a depolarizing shift in the half-inactivation potential and increased recovery from inactivation, consistent with a gain of function and increased channel activity.

Zonisamide was found to be useful in both the cases. The pharmacodynamics of zonisamide as an effective drug in myoclonic epilepsies stem from its effect on its blockade of T-type calcium channels, inhibition of slow sodium channels, and glutamate release.[11] Thus, pharmacogenomic implications of the identified mutations in the above probands carry therapeutic benefits and avoidance of SCB is paramount. In both patients, a combination of zonisamide with broad-spectrum agents such as valproate, levetiracetam, and benzodiazepines was found to be synergistic following failure of monotherapy in appropriate doses.

Acknowledgements

Medgenome Labs Private Ltd.; Strand Centre for Genomics and Personalized Medicine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Appendix 1 Top


A total of 158 genes associated with epilepsy were analyzed in the NGS panel used in this series: AARS, ACTB, ADRA2B, ADSL, AFG3L2, AGTR2, AKT3, ALDH7A1, ALG13, AMT, ARFGEF2, ASAH1, ASNS, ATP13A2, ATP1A2, ATP1A3, ATP6AP2, BRAT1, BRWD3, CACNA1A, CACNA1G, CACNA1H, CACNB4, CASK, CASR, CBL, CDKL5, CHD2, CHRNA7, CHRNB2, CLCN2, CLN3, CLN5, CLN6, CLN8, CNTNAP2, COL4A1, COL6A2, CPA6, CRH, CSTB, CTSD, D2HGDH, DCX, DIAPH1, DNAJC5, DNM1, DNM1L, DYNC1H1, DYRK1A, EFHC1, FARS2, FIG4, FLNA, FOLR1, GABRA1, GABRA6, GABRB3, GABRD, GABRG2, GATM, GLDC, GOSR2, GPHN, GRIN1, GRIN2A, GRIN2B, GRN, HCN1, HNRNPU, HSD17B10, IDH2, IER3IP1, JRK, KCNA1, KCND2, KCNJ10, KCNMA1, KCNQ2, KCNQ3, KCTD7, KIAA2022, L2HGDH, LGI1, LIAS, LMNB2, MAGI2, MBD5, MECP2, MED17, MEF2C, MFSD8, MOCS1, MTHFR, NEDD4L, NEU1, NHLRC1, NR2F1, NRXN1, PCDH19, PHF6, PHGDH, PIGA, PIGN, PIGO, PIGV, PNKP, PNPO, POLG, PPP1R3C, PPT1, PRICKLE1, PRICKLE2, PRRT2, PSEN1, PTEN, RBFOX1, RELN, ROGDI, SACS, SCARB2, SCN1A, SCN1B, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCN9A, SERPINI1, SLC25A22, SLC2A1, SLC6A1, SLC9A6, SMC1A, SNIP1, SPTAN1, SRPX2, ST3GAL3, ST3GAL5, STXBP1, SYNGAP1, TBC1D24, TBL1XR1, TCF4, TK2, TPP1, TSC2, UBE3A, USP9X, WDR45, WDR62, WWOX, ZEB2.



 
  References Top

1.
Delgado-Escueta AV, Medina MT, Bai DS, Fong CY, Tanaka M, Alonso ME. Genetics of idiopathic myoclonic epilepsies: An overview. In: Fahn S, Frucht SJ, Truong DD, Hallett M, editors. Myoclonus and paroxysmal dyskinesias. Advances in neurology, Vol 89. New York: Lippincott Williams & Wilkins; 2002. p 161–84.  Back to cited text no. 1
    
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Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 2012;53:1387-98.  Back to cited text no. 2
    
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Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: Mutations and mechanisms. Epilepsia 2010;51:1650-8.  Back to cited text no. 3
    
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Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet 2015;96:808-15.  Back to cited text no. 4
    
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Boiko T, Rasband MN, Levinson SR, Caldwell JH, Mandel G, Trimmer JS, et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 2001;30:91-104.  Back to cited text no. 5
    
6.
Liao Y, Anttonen AK, Liukkonen E, Gaily E, Maljevic S, Schubert S, et al. Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Na(v) 1.1. Epilepsia 2010;51:1669-78.  Back to cited text no. 6
    
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Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 2017;140:1316-36.  Back to cited text no. 7
    
8.
Aurlien D, Leren TP, Taubøll E, Gjerstad L. New SCN5A mutation in a SUDEP victim with idiopathic epilepsy. Seizure 2009;18:158-60.  Back to cited text no. 8
    
9.
Hartmann HA, Colom LV, Sutherland ML, Noebels JL. Selective localization of cardiac SCN5A sodium channels in limbic regions of rat brain. Nat Neurosci 1999;2:593-5.  Back to cited text no. 9
    
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Ho K, Melanson M. SCN5A Mutation Positivity in a patient with juvenile myoclonic epilepsy and congenital long-QT syndrome type 3. Neurology 2013;80:P05.090.  Back to cited text no. 10
    
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Welty TE. Zonisamide, In: Wyllie E, editor. Wyllie's Treatment of Epilepsy, Principles and Practice. 5th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2011. p. 723-30.  Back to cited text no. 11
    


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  [Figure 1], [Figure 2]



 

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