SCN1A Developmental and Epileptic Encephalopathy: From Seizures to Status Dystonicus

Pathogenic variations in the SCN1A gene, which encodes the Nav1.1 sodium channel, are associated with a spectrum of genetic epilepsies that classically include Dravet syndrome, Genetic Epilepsy With Febrile Seizures Plus, and Developmental And Epileptic Encephalopathies (DEE). Recent work has associated other epileptic encephalopathies, such as Epilepsy with Myoclonic-Atonic Seizures, Epilepsy of Infancy with Migrating Focal Seizures, Infantile Epileptic Spasm Syndrome, Lennox–Gastaut syndrome, Rett syndrome, and nonsyndromic epileptic encephalopathy, as well as non-epileptic disorders such as hemiplegic migraine, autism spectrum disorder, sudden death, and arthrogryposis multiplex congenita with the SCN1A gene.1 Specifically, SCN1A-DEE is characterized by severe early-infantile epilepsy, profound developmental and intellectual impairment, and often a hyperkinetic movement disorder.2 A 2-year-old boy, born to consanguineous parents, presented with drug-refractory epilepsy and developmental delay from early infancy, and recent-onset progressive dystonia for the past few months. He was term-born and made a smooth perinatal transition. At 3 months of age, he developed left-sided, focal, clonic, status epilepticus triggered by vaccination-related fever. Subsequently, he had recurrent, fever-triggered, focal seizures on either side once in 2–3 months, associated with prolonged post-ictal hemiparesis lasting for up to a week. In the second year of life, he started developing intermittent, abnormal, involuntary, hyperkinetic body movements. These appeared as generalized tightening and twisting postures involving the upper and lower limbs, neck, trunk and laryngeal muscles causing stridor. These dystonic movements were aggravated with fever, crying or procedural stimulation such as cannulation, while they completely subsided during sleep. There were no dance-like, writhing, sudden shock-like jerks or tremulous movements noticed in the child. These movements gradually worsened over the next few months and started occurring even at rest. At 27 months of age, he developed another episode of status epilepticus following a febrile viral illness. After seizure control, he developed progressively worsening dystonia and presented to our center. On examination, he had microcephaly (head circumference 44.5 cm, −3Z), axial hypotonia, normal muscle stretch reflexes, and persistent, generalized dystonia impairing airway maintenance and feeding (classified as status dystonicus grade 5 as per the Dystonia Severity Action Plan)3 (Video 1). As the child had early infantile-onset, recurrent, febrile status epilepticus (triggered by fever or vaccination), a provisional diagnosis of genetic DEE with hyperkinetic movement disorder such as Dravet syndrome (SCN1A-DEE) or GNAO1-related disorder was considered. He required prolonged mechanical ventilation, sedation and antimicrobial agents to treat health-care associated sepsis and pneumonia. In view of respiratory failure he was intubated and put on mechanical ventilation and started on intravenous midazolam (up to 4 mcg/kg/min). In parallel, a stepwise escalation of enteral anti-dystonic therapy was undertaken, including trihexyphenidyl (up to 16 mg/day), baclofen (up to 40 mg/day), and clonidine (up to 10 μg/kg/day). Gradual clinical stabilization permitted transition from invasive mechanical ventilation to non-invasive positive pressure ventilation via BiPAP. Intravenous sedation was converted to enteral benzodiazepines. Despite partial clinical improvement, dystonia persisted with only marginal benefit following the sequential addition of gabapentin, levodopa–carbidopa, tetrabenazine, and risperidone. Resperidone was added in this case as an add on therapy with evidence supporting its efficacy in idiopathic and symptomatic dystonia due to greater 5HT2A blockade than D2 receptor blockade.4 However, sustained control could not be achieved, and the patient continued to experience recurrent dystonic exacerbations requiring intermittent intravenous benzodiazepine boluses complicated by healthcare associated infections. Gradually dystonic exacerbations subsided over the next 4 weeks and at the time of discharge dystonia was intermittent triggered by crying and painful stimuli. Magnetic resonance imaging (MRI) of the brain revealed diffuse cortical atrophy with ventricular dilatation (Fig. 1). Sequencing revealed a pathogenic, heterozygous, missense variant c.5347G>A in exon 29 of SCN1A gene that results in the amino acid substitution p.Ala1783Thr. This variant (Variation ID: 68570) and another variant with same protein codon but different amino acid change (c.5348C>T/p.Ala1783Val) (Variation ID: 68571) has been reported in ClinVar as Pathogenic and detected in individuals with Dravet syndrome.5 The variant was not detected in the parents. Functional impact of this mutation was found to have mixed effects.6 Movement disorders in DEE remain underrecognized due to the dramatic presentation of epilepsy and developmental problems. Hyperkinetic movement disorders in this group are being increasingly recognized, specifically with SCN1A, SCN2A, SCN8A, FOXG1, STXBP1, GNAO1, ARX, and DNM1 genes.7 Van der Veen et al have observed that patients with pathogenic variations causing abnormalities in channel functioning (channelopathies) or in synaptic vesicle trafficking have a higher propensity for dystonia, whereas individuals with pathogenic variations affecting transcriptional regulation demonstrate stereotypies.8 Underlying developmental status may also predict the type of movement disorder: ataxia occurred more frequently in ambulatory patients with mild to moderate intellectual impairment, whereas dystonias occurred in severely disabled non-ambulatory patients.8 SCN1A variants may result in loss-of-function, and less commonly, gain-of-function effects. Gain-of-function variations have been commonly associated with hyperkinetic movement disorders including dystonia and chorea, co-occurring with seizures. Although loss-of-function mutations are the defining genetic mechanism in Dravet syndrome, movement disorders can also occur in this context, particularly in cases involving mixed gain- and loss-of-function effects. Epilepsy associated with loss-of-function variants in SCN1A-related DEE primarily results from impaired GABAergic interneuron activity, leading to neuronal hyperexcitability. In contrast, gain-of-function variants are thought to cause hyperpolarizing shifts in channel activation, increasing persistent sodium (window) current, lowering action potential threshold, and enhancing channel availability; however, the precise epileptogenic mechanisms remain incompletely understood and warrant further investigation in experimental models.9 Movement disorders in SCN1A-DEE result from widespread disruption of neuronal networks. These variants impair the function of the NaV1.1 sodium channel, leading to a marked imbalance between excitatory and inhibitory neurotransmission, predominantly due to loss-of-function in GABAergic interneurons. The consequent network dysregulation and maladaptive remodeling contribute to the emergence of movement disorders, which may occur independently of, or in association with epilepsy.9 Although the incidence of Dravet syndrome has been reported between 1:15,700 and 1:40,000 live births in the US population,10 the exact estimates of the co-occurring movements disorders in SCN1A-DEE are not yet available probably due to the lack of registries, recent awareness about the movement disorder phenotypes and heterogenous descriptions in literature. Movement disorder phenomenology described with SCN1A-DEE include eyelid stereotypies, variable combinations of choreoathetosis, dystonia, and oral dyskinesia, and hyperekplexia (neonatal DEE, arthrogryposis congenita, and scoliosis).2, 7, 11 Ohashi et al were among the first to describe an infant with early-onset epilepsy accompanied by a hyperkinetic movement disorder, characterized by prominent hand stereotypies, choreiform movements, and generalized dyskinesia due to a novel SCN1A variation.7 Subsequently, Sadleir et al provided the first detailed characterization of a gain-of-function SCN1A-related DEE, identifying a distinct early-onset phenotype associated with the recurrent Thr226Met variant, in which all nine patients exhibited epilepsy and prominent movement disorders, predominantly dystonia and/or choreoathetosis, within the first 2 years of life.2 Our case expands the phenotype of SCN1A-DEE. Progressive dystonia with status dystonicus as a complication is a rare presentation of SCN1A-DEE with underlying genetic basis demonstrating a mix of gain- and loss-of-function effects on the SCN1A channel. This underscores the need for a deeper insight into the physiological consequences of specific pathogenic variants. (1) Study: A. Conceptualization, B. Interpretation of results; (2) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. A.R.: 1A, 2A. A.G.S.: 2A, 2B. J.K.S.: 2B. S.V.: 1B. P.S.: 1B. All authors approved the final version of the manuscript. None. Ethical Compliance Statement: This study does not require Institutional Ethics committee approval. Informed patient consent was taken regarding publication of patient video and clinical details. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work and the authors declare that there are no funding sources or conflict of interest relevant to this work. Financial Disclosures for the Previous 12 Months: RA: The authors declare that there are no funding sources or conflicts of interest relevant to this work. AGS received funding from Indian Council of Medical Research (ICMR) via PGIMER, Chandigarh. JKS received financial grant from Indian Council of Medical Research (ICMR) via PGIMER, Chandigarh. SV: The authors declare that there are no funding sources or conflicts of interest relevant to this work. PS: The authors declare that there are no funding sources or conflicts of interest relevant to this work. Author disclosures are available in the Supporting Information. Data sharing not applicable to this article as no datasets were generated or analysed during the current study. Data S1. Coi final all. 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