The incidence of SCN1A‐related Dravet syndrome in Denmark is 1:22,000: A population‐based study from 2004 to 2009

Dravet syndrome is a severe infantile‐onset epileptic encephalopathy associated with mutations in the sodium channel alpha‐1 subunit gene SCN1A. We aimed to describe the incidence of Dravet syndrome in the Danish population. Based on a 6‐year birth cohort from 2004 to 2009, we propose an incidence of 1:22,000, which is higher than what has been established earlier. We identified 17 cases with SCN1A mutation–positive Dravet syndrome. Fifteen patients were found, by conventional Sanger sequencing. Two additional patients with clinical Dravet syndrome, but without a detectable SCN1A mutation by Sanger sequencing, were diagnosed with a SCN1A mutation after using a targeted next‐generation sequencing gene panel.     

When should clinicians order genetic testing for Dravet syndrome?

The role of neuronal voltage-gated sodium channel, α-1 subunit (SCN1A) gene mutations in Dravet syndrome is well-established. With a broader phenotype than initially described, some patients lack features of Dravet syndrome as defined by the International League Against Epilepsy. We evaluated the predictive value of International League Against Epilepsy criteria for a positive mutation in a cohort of consecutively tested children. Mutations of SCN1A were evident in 16 of 69 children. Exhibiting ≥4 International League Against Epilepsy criteria demonstrated 100% sensitivity. Seven criteria (resistance to multiple antiepileptic drugs, multiple seizure types, abnormal electroencephalogram features, exacerbation with hyperthermia, normal development before seizure onset, seizures beginning before age 1 year, and psychomotor retardation) were present in ≥85% of mutation-positive cases. The three criteria that best predicted a mutation in SCN1A included exacerbation with hyperthermia, normal development before seizure onset, and the appearance of ataxia, pyramidal signs, or interictal myoclonus. We have demonstrated a high-sensitivity testing strategy for detecting mutations of SCN1A in children with suspected Dravet syndrome.     

SCN8A encephalopathy: Mechanisms and models

De novo mutations of the neuronal sodium channel SCN8A have been identified in approximately 2% of individuals with epileptic encephalopathy. These missense mutations alter the biophysical properties of sodium channel Nav1.6 in ways that lead to neuronal hyperexcitability. We generated two mouse models carrying patient mutations N1768D and R1872W to examine the effects on neuronal function in vivo. The conditional R1872W mutation is activated by expression of CRE recombinase, permitting characterization of the effects of the mutation on different classes of neurons and at different points in postnatal development. Preclinical drug testing in these mouse models provides support for several new therapies for this devastating disorder. In contrast with the gain‐of‐function mutations in epilepsy, mutations of SCN8A that result in partial or complete loss of function are associated with intellectual disability and other disorders.     

A novel muscle sodium channel mutation causes painful congenital myotonia

Mutations in the skeletal muscle voltage-gated sodium channel α-subunit gene (SCN4A) have been associated with a spectrum of inherited nondystrophic myotonias and periodic paralyses. Most disease-associated SCN4A alleles occur in portions of the gene that encode the third and fourth repeat domains with the conspicuous absence of mutations in domain 1. Here we describe a family segregating an unusual autosomal dominant congenital myotonia associated with debilitating pain especially severe in the intercostal muscles. A novel SCN4A mutation causing the replacement of Val⁴⁴⁵ in the sixth transmembrane segment of domain 1 with methionine was discovered in all affected individuals and is the likely genetic basis for the syndrome. Myotonia was resistant to treatment; however, the most severely affected family member responded dramatically to the sodium channel blocking agent flecainide.     

Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome

Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS⁺) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS⁺ families could be explained by highly penetrant SCN9A mutations.     

A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures

Generalised (genetic) epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with various phenotypes. The majority of individuals with GEFS+ have generalised seizure types, in addition to febrile seizures (FS) or febrile seizures plus (FS+), defined as either continued FS after 6 years of age or afebrile seizures following FS. A 27‐year‐old man with no history of FS/FS+ experienced intractable generalised convulsive seizures. The patient's father had a history of similar seizures during puberty and the patient's siblings had only FS. No individual in the family had both generalised seizures and FS/FS+, although GEFS+ might be considered to be present in the family. Analysis of SCN1A, a sodium channel gene, revealed a novel mutation (c.3250A>T [S1084C]) in the cytoplasmic loop 2 of SCN1A in both the patient and his father. Most previously reported SCN1A mutations in GEFS+ patients are located in the conserved homologous domains of SCN1A, whereas mutations in the cytoplasmic loops are very rare. SCN1A gene analysis is not commonly performed in subjects with generalised seizures without FS. SCN1A mutation may be a clinically‐useful genetic marker in order to distinguish GEFS+ patients from those with classic idiopathic generalised epilepsy, even if they present an atypical clinical picture.     

Dravet syndrome: Seizure control and gait in adults with different SCN1A mutations

Purpose: Dravet syndrome (DS) is an aggressive epileptic encephalopathy. Pharmacoresistant seizures of several types plague most patients with DS throughout their lives. Gait difficulties are a common, but inconsistent finding. The majority of cases are caused by mutations in the SCN1A gene, but little information is available about how particular mutations influence the adult phenotype. The purpose of this study is to correlate different types of SCN1A mutations and (1) seizure control, (2) occurrence of convulsive status epilepticus (cSE), and (3) the presence of crouch gait in adult patients. Methods: In a cohort of 10 adult patients with DS caused by SCN1A mutations, we investigated seizure frequency, history of cSE, and gait. All patients were identified in the epilepsy clinic between 2009 and 2011. SCN1A mutations were divided into four different groups based on location or effect of the mutation. Retrospective chart review and recent physical examination were completed in all cases. Key Findings: All patients had a pathogenic mutation in the SCN1A gene. Four SCN1A mutations have not been described previously. Greater than 90% seizure reduction was observed (compared to childhood frequency) in six of seven patients with missense mutations in the pore‐forming region (PFR) of the Na_v1.1 protein (group A) and nonsense mutations (group B). One patient with a splice‐site mutation (group C) and another with a mutation outside the PFR (group D) became free of all types of seizures. cSE after the age of 19 years was observed in only one patient. Crouch gait, without spasticity, is identified as an element of the adult DS phenotype. However, only one half of our adult DS cohort demonstrated crouch gait. This feature was observed in five of seven patients from groups A and B. Significance: This study shows that seizure control improves and cSE become less frequent in DS as patients age, independent of their SCN1A mutation type. Complete seizure freedom was seen in two patients (groups C and D). Finally, this study shows that in DS, crouch gait can be observed in up to 50% of adults with SCN1A mutation. Although no definite statistical correlations could be made due to the small number of patients, it is interesting to note that crouch gait was observed only in those patients with nonsense mutations or mutations in the PFR. Future studies with larger cohorts will be required to formally assess an association of gait abnormalities with particular SCN1A mutations.     

A homozygous mutation of voltage‐gated sodium channel βI gene SCN1B in a patient with Dravet syndrome

Dravet syndrome is a severe form of epileptic encephalopathy characterized by early onset epileptic seizures followed by ataxia and cognitive decline. Approximately 80% of patients with Dravet syndrome have been associated with heterozygous mutations in SCN1A gene encoding voltage‐gated sodium channel (VGSC) α_I subunit, whereas a homozygous mutation (p.Arg125Cys) of SCN1B gene encoding VGSC β_I subunit was recently described in a patient with Dravet syndrome. To further examine the involvement of homozygous SCN1B mutations in the etiology of Dravet syndrome, we performed mutational analyses on SCN1B in 286 patients with epileptic disorders, including 67 patients with Dravet syndrome who have been negative for SCN1A and SCN2A mutations. In the cohort, we found one additional homozygous mutation (p.Ile106Phe) in a patient with Dravet syndrome. The identified homozygous SCN1B mutations indicate that SCN1B is an etiologic candidate underlying Dravet syndrome.     

De novo truncating mutation in SCN1A as a cause of febrile seizures plus (FS+)

SCN1A is one of the most relevant epilepsy genes. In general, de novo severe mutations, such as truncating mutations, lead to a classic form of Dravet syndrome (DS), while missense mutations are associated with both DS and milder phenotypes within the GEFS+ spectrum, however, these phenotype‐genotype correlations are not entirely consistent. Case report. We report an 18‐year‐old woman with a history of recurrent febrile generalized tonic‐clonic seizures (GTCS) starting at age four months and afebrile asymmetric GTCS and episodes of arrest, suggestive of focal impaired awareness seizures, starting at nine months. Her psychomotor development was normal. Sequencing of SCN1A revealed a heterozygous de novo truncating mutation (c.5734C>T, p.Arg1912X) in exon 26. Conclusion. Truncating mutations in SCN1A may be associated with milder phenotypes within the GEFS+ spectrum. Accordingly, SCN1A gene testing should be performed as part of the assessment for sporadic patients with mild phenotypes that fit within the GEFS+ spectrum, since the finding of a mutation has diagnostic, therapeutic and genetic counselling implications.     

Mutations of the SCN1A gene in acute encephalopathy

Purpose: Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthema subitum. It occurs worldwide, but is most prevalent in East Asia. Recently, there have been sporadic case reports of epilepsy/febrile seizure and acute encephalopathy with a neuronal sodium channel alpha 1 subunit (SCN1A) mutation. To determine whether SCN1A mutations are a predisposing factor of acute encephalopathy, we sought to identify SCN1A mutations in a large case series of acute encephalopathy including various syndromes. Methods: We analyzed the SCN1A gene in 87 patients with acute encephalopathy, consisting of 20 with acute necrotizing encephalopathy (ANE), 61 with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), and six with nonspecific (unclassified) acute encephalopathy. Key Findings: Three patients had distinct point mutations. Two of them had epileptic seizures prior to acute encephalopathy. Clinical and neuroradiologic findings of acute encephalopathy were diverse among the three patients, although all had a prolonged and generalized seizure at its onset. The first patient with V982L had partial epilepsy and AESD. The second patient with M1977L had febrile seizures and nonspecific acute encephalopathy. The third patient with R1575C had no seizures until the onset of ANE. M1977L was a novel mutation, whereas the remaining two, V982L and R1575C, have previously been reported in cases of Dravet syndrome and acute encephalopathy, respectively. Significance: These findings provide further evidence that SCN1A mutations are a predisposing factor for the onset of various types of acute encephalopathy.     

A CACNB4 mutation shows that altered Ca(v)2.1 function may be a genetic modifier of severe myoclonic epilepsy in infancy

Mutations of SCN1A, encoding the voltage-gated sodium channel α1 subunit, represent the most frequent genetic cause of severe myoclonic epilepsy in infancy (SMEI). The purpose of this study was to determine if mutations in other seizure susceptibility genes are also present and could modify the disease severity. All coding exons of SCN1B, GABRG2, and CACNB4 genes were screened for mutations in 38 SCN1A-mutation-positive SMEI probands. We identified one proband who was heterozygous for a de novo SCN1A nonsense mutation (R568X) and another missense mutation (R468Q) of the CACNB4 gene. The latter mutation was inherited from his father who had a history of febrile seizures. An electrophysiological analysis of heterologous expression system exhibited that R468Q-CACNB4 showed greater Ba²⁺ current density compared with the wild-type CACNB4. The greater Ca_v2.1 currents caused by the R468Q-CACNB4 mutation may increase the neurotransmitter release in the excitatory neurons under the condition of insufficient inhibitory neurons caused primarily by the SCN1A mutation.     

SCN1A testing for epilepsy: Application in clinical practice

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage‐gated sodium channels (protein name: Na_v1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.     

Infantile epileptic encephalopathy with a hyperkinetic movement disorder and hand stereotypies associated with a novel SCN1A mutation

We report a female patient who presented with intractable epileptic seizures, profound developmental delay since early infancy, and hyperkinetic movements with hand stereotypies. The patient initially developed focal seizures with multiple foci at 3 months of age. Thereafter, the seizures evolved to frequent episodes of hyperthermia‐induced status epilepticus. A novel de novo SCN1A mutation was identified by whole‐exome sequence analysis. This case demonstrates that SCN1A mutations may cause movement disorders as an atypical phenotype and the case history of this patient may expand our understanding of the clinical spectrum of SCN1A‐associated epileptic encephalopathy. [Published with video sequences]     

No mutations in the voltage‐gated NaV1.7 sodium channel α1 subunit gene SCN9A in familial complex regional pain syndrome

Background: Mutations in the voltage‐gated Na_V1.7 Na⁺ channel α1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. Methods: We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. Results: No causal gene mutations were identified in the SCN9A gene in any of the patients. Conclusions: Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS.     

A novel mutation of α-galactosidase A gene causes Fabry disease mimicking primary erythromelalgia in a Chinese family

Purpose: Fabry disease is an X-linked genetic disorder caused by the mutations of α-galactosidase A (GLA, MIM 300644) gene presenting with various clinical symptoms including small-fiber peripheral neuropathy and limb burning pain. Here, we reported a Chinese pedigree with the initial diagnosis of primary erythromelalgia in an autosomal dominant (AD)-inherited pattern. Methods: Mutation analysis of SCN9A and GLA genes by direct sequencing and functional analysis of a novel mutation of GLA in cells were performed. Results: Our data did not show any pathological mutations in SCN9A gene; however, a novel missense mutation c.139T>C (p.W47R) of GLA was identified in a male proband as well as two female carriers in this family. Enzyme assay of α-galactosidase A activity showed deficient enzyme activity in male patients and female carriers, further confirming the diagnosis of Fabry disease. Finally, a functional analysis indicated that the replacement of the 47th amino acid tryptophan (W47) with arginine (W47R) or glycine (W47G) led to reduced activity of α-galactosidase A in 293T cells. Therefore, these findings demonstrated that the novel mutation p.W47R of GLA is the cause of Fabry disease. Conclusions: Because Fabry disease and primary erythromelalgia share similar symptoms, it is a good strategy for clinical physicians to perform genetic mutation screenings on both SCN9A and GLA genes in those patients with limb burning pain but without a clear inheritant pattern.     

Dravet syndrome: patients with co-morbid SCN1A gene mutations and mitochondrial electron transport chain defects

PurposeTo review our cohort of patients with Dravet syndrome and determine if patients with SCN1A mutations can also express mitochondrial disease due to electron transport chain dysfunction.MethodsA retrospective chart review was used to describe clinical manifestations and retrieve biochemical testing, neuroimaging, gene sequencing, and electroencephalographic results of patients expressing both mitochondrial disease and Dravet syndrome.ResultsTwo children were found to have pathological mutations in the SCN1A gene and defects in mitochondrial electron transport chain complex activity. Both developed early febrile and medically intractable afebrile seizures with resulting neurocognitive decline. In the first patient, a muscle biopsy demonstrated complex IV dysfunction and in the second patient, complex III dysfunction. Patient 1 had more difficult to control seizures, and had features consistent with severe autism. Patient 2, who had earlier control and less severe seizures, did not have features of autism. Patient 1 had SCN1A missense mutation, c. 3734 G > A and patient 2 had a mutation, c. 3733 C > T, which produces a truncation mutation.ConclusionOur two patients underscore the need to rule out possible co-morbid mitochondrial disease and Dravet syndrome. The treatment of seizures for each is different, with valproic acid being first line treatment in Dravet syndrome and contraindicated in many mitochondrial diseases, due to possible induction of liver failure and death. Failure to pursue complete diagnostic evaluation might influence medication choice, possible seizure control, and developmental outcomes.     

Painful neuropathies: the emerging role of sodium channelopathies

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage‐gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na_V1.7, Na_V1.8, and Na_V1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain‐of‐function SCN9A mutations. Recent studies have expanded this spectrum with gain‐of‐function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch‐clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell‐type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length‐dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain‐of‐function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.     

Emergence of lingual dystonia and strabismus in early-onset SCN8A self-limiting familial infantile epilepsy

Pathogenic variants in SCN8A are associated with a broad phenotypic spectrum, including Self-Limiting Familial Infantile Epilepsy (SeLFIE), characterized by infancy-onset age-related seizures with normal development and cognition. Movement disorders, particularly paroxysmal kinesigenic dyskinesia typically arising after puberty, may represent another core symptom. We present the case of a 1-year-old girl with a familial disposition to self-limiting focal seizures from the maternal side and early-onset orofacial movement disorders associated with SCN8A-SeLFIE. Brain MRI was normal. Genetic testing revealed a maternally inherited SCN8A variant [c.4447G > A; p.(Glu1483Lys)]. After the introduction of valproic acid, she promptly achieved seizure control as well as complete remission of strabismus and a significant decrease in episodes of tongue deviation. Family history, genetic findings, and epilepsy phenotype are consistent with SCN8A-SeLFIE. Movement disorders are an important part of the SCN8A phenotypic spectrum, and this case highlights the novel early-onset orofacial movement disorders associated with this condition. The episodes of tongue deviation and protrusion suggest focal oromandibular (lingual) dystonia. Additionally, while infantile strabismus or esophoria is a common finding in healthy individuals, our case raises the possibility of an ictal origin of the strabismus. This study underscores the importance of recognizing and addressing movement disorders in SCN8A-SeLFIE patients, particularly the rare early-onset orofacial manifestations. It adds to the growing body of knowledge regarding the diverse clinical presentations of SCN8A-associated disorders and suggests potential avenues for clinical management and further research.     

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.Key Words: SCN8A, phenytoin, epileptic encephalopathy, sodium channel blockers