Scn8a-Related Epilepsy With Encephalopathy

Watchlist
Retrieved
2021-01-18
Source
Trials
—
Genes
Drugs
—

Summary

Clinical characteristics.

SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.

Diagnosis/testing.

The diagnosis is established in a proband with encephalopathy and epilepsy and identification of a de novo pathogenic variant in SCN8A on molecular genetic testing.

Management.

Treatment of manifestations: Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for SCN8A-related epilepsy with encephalopathy and aware of how it differs from treatment of similar disorders. Vigorous attempts to control seizures are warranted. Several studies suggest a favorable response to sodium channel blockers.

Surveillance: Periodic evaluation for neurologic, cognitive, and/or behavioral deterioration; monitoring with EEG and other modalities such as video EEG telemetry or ambulatory EEG when new or different seizure types are suspected. Because of the increased risk of SUDEP, some families use oxygen monitoring during sleep.

Agents/circumstances to avoid: Several families of affected individuals report worsening of seizures with levetiracetam.

Genetic counseling.

SCN8A-related epilepsy with encephalopathy is expressed in an autosomal dominant manner. Most affected individuals have a de novo pathogenic variant and typically do not reproduce. While the risk to future pregnancies is presumed to be low, some parents of an affected child may wish to consider prenatal testing or preimplantation genetic testing in future pregnancies as the risk may be slightly greater than in the general population because of the possibility of parental germline mosaicism.

Diagnosis

Suggestive Findings

SCN8A-related epilepsy with encephalopathy should be suspected in individuals with early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with ongoing epileptiform activity), particularly those with the following epilepsy features, seizure types, and/or epilepsy syndromes.

Epilepsy features

  • Seizure onset in the first 18 months of life (mean age 4 months)
  • Focal clonic seizures evolving into bilateral convulsive seizures
  • Development of multiple seizure types
  • Motor abnormalities including hypotonia
  • Movement disorders including dystonia, ataxia, choreoathetosis

Seizure types

  • Intractable childhood epilepsy with generalized tonic-clonic seizures
  • Infantile spasms
  • Absence and focal seizures

Epilepsy syndromes

  • Lennox-Gastaut syndrome
  • West syndrome
  • Early-onset epilepsy with hypotonia, movement disorders, and/or intellectual disability (e.g., Dravet syndrome)

Establishing the Diagnosis

The diagnosis of SCN8A-related epilepsy with encephalopathy is established in a proband with encephalopathy and epilepsy by identification of a de novo pathogenic variant in SCN8A through molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include targeted gene testing (multigene panel) or genomic testing (comprehensive genomic sequencing).

Targeted gene testing requires the clinician to develop a hypothesis about which specific gene(s) are likely to be involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with SCN8A encephalopathy with epilepsy are diagnosed by following recommended testing (multigene panel) or testing to consider (comprehensive genomic sequencing). Note that testing of SCN8A alone (i.e., single-gene testing) is rarely used.

Recommended Testing

A multigene panel that includes SCN8A and other genes of interest (see Differential Diagnosis) is the recommmmended approach. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype is indistinguishable from other inherited disorders (or the phenotype alone is insufficient to support focused gene testing). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SCN8A-Related Encephalopathy with Epilepsy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
SCN8ASequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5Unknown, none reported to date 4
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

In the first 100 individuals with SCN8A-related encephalopathy with epilepsy, all SCN8A pathogenic variants were missense variants with the exception of one splice site variant predicted to cause an in-frame deletion [Rauch et al 2012; Veeramah et al 2012; Carvill et al 2013; Allen et al 2013; de Kovel et al 2014; Estacion et al 2014; Ohba et al 2014; Vaher et al 2014; Blanchard et al 2015; Dyment et al 2015; Fitzgerald et al 2015, Fung et al 2015; Kong et al 2015a; Larsen et al 2015; Mercimek-Mahmutoglu et al 2015; Olson et al 2015; Singh et al 2015; Takahashi et al 2015; Wagnon et al 2015a; Boerma et al 2016; M Hammer, unpublished data].

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

SCN8A pathogenic variants have been associated with developmental delay prior to and/or after onset of seizures, intellectual disability without seizures, and epileptic encephalopathy.

SCN8A-related epilepsy with encephalopathy is an early-onset, intractable epilepsy characterized by multiple seizure types and developmental delay. To date 50 individuals with a de novo SCN8A pathogenic variant have been reported [Rauch et al 2012, Veeramah et al 2012, Allen et al 2013, Carvill et al 2013, de Kovel et al 2014, Estacion et al 2014, Ohba et al 2014, Vaher et al 2014, Blanchard et al 2015, Dyment et al 2015, Fitzgerald et al 2015, Fung et al 2015, Kong et al 2015a, Larsen et al 2015, Mercimek-Mahmutoglu et al 2015, Olson et al 2015, Singh et al 2015, Takahashi et al 2015, Wagnon et al 2015a, Boerma et al 2016].

The most common clinical features of SCN8A-related epilepsy with encephalopathy are described below. Of note, sudden setbacks of unknown cause are common.

Seizures. In 48 of the 50 affected individuals reported to date age of onset of seizures ranged from the first day of life to age 22 months (median age: 4 months; mean age: 4.7 months). Of note, prenatal onset of seizures may occur as some mothers reported unusual "drumming" movements in the later stages of pregnancy [Singh et al 2015].

Initial seizure type varies, and most affected individuals develop additional seizure types, including the following:

  • Focal clonic seizures evolving to a bilateral convulsive seizure
  • Afebrile generalized tonic clonic seizures
  • Tonic seizures
  • Infantile spasms
  • Myoclonic seizures

Although both convulsive and non-convulsive status epilepticus appear to be common [Larsen et al 2015], they are not as common as in Dravet syndrome.

Seizure frequencies range from hundreds per day to fewer than one per month.

Most affected individuals have refractory seizures and require polytherapy (see Treatment of Manifestations).

Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth [Larsen et al 2015]. Many affected individuals experience marked slowing or arrest in development either for no apparent reason or after an event that occurred before the developmental decline, such as a change in seizure type or change in medication.

Approximately half of affected children learn to sit and walk unassisted; the remainder are non-ambulatory. Ataxia and sudden loss of mobility are common in those who are ambulatory.

The oldest patient of whom the authors are aware is 47 years old; the majority of diagnosed individuals are younger than age 20 years. For the several who are in their teens, cognitive and motor disabilities persist.

Language is frequently affected. The majority of affected individuals speak few or no words.

Intellectual disability ranges from mild to severe, with about half of affected individuals having severe intellectual disability. Autistic features are noted in some [Larsen et al 2015].

Movement abnormalities including hypotonia, dystonia, choreoathetosis, ataxia, spasticity, and increased startle have been described in some affected individuals.

Startle and sleep problems. Many children are hyper-alert as infants (i.e., more awake and aware of their surroundings than typical infants) and are easily startled. For example, Singh et al [2015] reported a newborn with jittery movements shortly after birth and a pathologically exaggerated startle response to tactile and acoustic stimuli, findings that prompted a suspicion of hyperekplexia. The hyper-alert sleep appears to make it difficult for the infant to settle into a deep, healthy sleep. These findings have been anecdotally reported in several other individuals with SCN8A-related encephalopathy with epilepsy.

Associated medical problems, reported in some affected individuals, can include the following:

  • Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
  • Hearing problems
  • Bone fractures, often associated with prolonged seizures
  • Laryngomalacia
  • Scoliosis
  • Microcephaly
  • Cortical visual impairment
  • Gum hyperplasia secondary to antiepileptic drugs (AEDs)

Sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of published cases [Veeramah et al 2012, Estacion et al 2014, Kong et al 2015a, Larsen et al 2015]. The cause of SUDEP is unknown, but may be related to prolonged seizures, cardiac abnormalities, or brain stem dysfunction. SUDEP can occur at any age.

EEG. Early on the EEG may be normal or exhibit focal or multifocal epileptiform activity. The EEG tends to evolve over time, often showing moderate to severe background slowing and focal or multifocal sharp waves or spikes, most often in the temporal regions. Some show almost continuous delta slowing in the temporo-parietal-occipital regions, with superimposed beta frequencies and bilateral asynchronous spikes or sharp waves [Larsen et al 2015].

Brain MRI is usually normal at the onset of seizures; however, abnormal findings may include cerebral atrophy and hypoplasia of the corpus callosum. Some affected individuals have been shown to have developed cerebral or cerebellar atrophy in follow-up studies [Larsen et al 2015, Singh et al 2015].

Genotype-Phenotype Correlations

There is no obvious correlation between the position of an SCN8A pathogenic variant and the seizure onset, seizure type, or clinical severity. Most pathogenic variants are located in the transmembrane segments of the channel.

Notable similarities in age of onset and movement impairment were reported in two severely affected, unrelated individuals with the same de novo pathogenic variant p.Ile1327Val [Vaher et al 2014, Singh et al 2015]; in contrast, however, multiple individuals with the pathogenic variant p.Arg1617Gln had different ages of onset and disease severity [Wagnon & Meisler 2015].

Penetrance

Penetrance for SCN8A-related epilepsy with encephalopathy is unknown but assumed to be complete.

  • All SCN8A pathogenic variants identified to date have been de novo or inherited from a parent with a somatic mosaic pathogenic variant that included the germline.
  • None of the SCN8A pathogenic variants have been seen in unaffected individuals, including controls in various studies and the ExAC database of ~60,000 genomes (exac.broadinstitute.org).

Prevalence

The prevalence of SCN8A-related epilepsy with encephalopathy is not known.

The frequency of SCN8A pathogenic variants among individuals with epileptic encephalopathy was 13/1557 (close to 1%) in four independent studies, each of which included several hundred individuals [Allen et al 2013, Carvill et al 2013, Larsen et al 2015, Mercimek-Mahmutoglu et al 2015].

Differential Diagnosis

The clinical features associated with a SCN8A pathogenic variant overlap significantly with other genetic (and non-genetic) epileptic encephalopathies. The differential diagnosis should include all genes known to be associated with early infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series).

Structural abnormalities of the brain that cause epileptic encephalopathy should be included in the differential diagnosis and can be identified by brain MRI.

Treatable neurometabolic disorders causing early infantile-onset epileptic encephalopathy that should be considered in the differential diagnosis include:

  • Pyridoxine-dependent epilepsy
  • Pyridoxamine 5'-phosphate oxidase deficiency (OMIM 610090)
  • Biotinidase deficiency
  • Glucose transporter 1 deficiency syndrome
  • Creatine deficiency syndromes
  • Holocarboxylase synthetase deficiency (OMIM 253270)
  • Serine biosynthesis disorders including:
    • Phosphoglycerate dehydrogenase deficiency (OMIM 601815)
    • Phosphoserine aminotransferase deficiency (OMIM 610992)
    • Phosphoserine phosphate deficiency (OMIM 614023)

Dravet syndrome is an infantile epileptic encephalopathy characterized by hemiclonic or generalized seizures that are often triggered by fever. More than 80% of individuals with Dravet syndrome have a de novo pathogenic variant in SCN1A (a related sodium channel gene) that results in loss of function due to protein truncation (60%) or pathogenic missense variants that inactivate the channel [Marini et al 2011]. The distinction between epilepsy caused by mutation of SCN1A and epilepsy caused by mutation of SCN8A is important because sodium channel blockers should be avoided in Dravet syndrome whereas they may be beneficial in SCN8A-related epilepsy with encephalopathy (see Treatment of Manifestations).

Distinctions between SCN8A-related epilepsy with encephalopathy and Dravet syndrome include:

  • Age of onset. The mean age of onset is similar but the range of 0 days to 22 months in SCN8A-related epilepsy with encephalopathy is broader than that seen in Dravet syndrome.
  • Febrile seizures. Susceptibility to seizures with fever is common in Dravet syndrome, but rare in SCN8A-related encephalopathy with epilepsy.
  • Infantile spasms. Many patients with SCN8A-related epilepsy with encephalopathy present with spasms, which are not a feature of Dravet syndrome.
  • Myoclonic seizures. Patients with SCN8A-related epilepsy with encephalopathy rarely have myoclonic seizures, which are common in Dravet syndrome.
  • Hypotonia and movement disorders are common in patients with SCN8A-related encephalopathy with epilepsy, but are not typical of Dravet syndrome.
  • EEG findings. Generalized spike wave, a hallmark of Dravet syndrome after age one to two years, is not typical in SCN8A-related encephalopathy with epilepsy.
  • Medications. Sodium channel blockers such as carbamazepine, oxcarbazepine, and phenytoin appear to be the most efficacious antiepileptic drug (AED) for SCN8A-related epilepsy with encephalopathy [Larsen et al 2015, Boerma et al 2016], while many patients with Dravet syndrome do worse on sodium channel blockers.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SCN8A-related encephalopathy with epilepsy, the following evaluations are recommended:

  • Neurologic examination including:
    • EEG, which may provide an assessment of the overall degree of epileptic encephalopathy and seizure type
    • Brain MRI if not previously performed
  • Cognitive and behavioral neuropsychological evaluation
  • ECG to assess for cardiac arrhythmias, which have been identified in some patients with mutation of genes encoding other sodium channel subunits and may increase the risk of sudden unexpected death in epilepsy (SUDEP)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No published treatment guidelines exist.

Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for SCN8A-related epilepsy with encephalopathy and how it differs from treatment of similar disorders (e.g., Dravet syndrome; see SCN1A-Related Seizure Disorders and Differential Diagnosis).

Vigorous attempts to control seizures with drug polytherapy are warranted because children with SCN8A-related epilepsy with encephalopathy are at risk for sudden unexplained death in epilepsy (SUDEP) as well as prolonged acute seizures that may cause permanent injury [Chipaux et al 2010, Takayanagi et al 2010].

Sodium channel blockers. Several studies suggest that patients with SCN8A-related epilepsy with encephalopathy respond favorably to the class of antiepileptic drugs (AEDs) that block sodium channels; these include phenytoin, valproate, carbamazepine, lacosamide, lamotrigine, rufinamide, and oxcarbazepine [Kong et al 2015b, Larsen et al 2015, Boerma et al 2016]. The effectiveness of sodium channel blockers is consistent with the activating effects of most SCN8A pathogenic variants [Wagnon & Meisler 2015, Wagnon et al 2015a, Wagnon et al 2015b]. Most patients are maintained on multiple medications with incomplete seizure control. One study of four patients reported a positive response to high doses of phenytoin [Boerma et al 2016].

Other AEDs

  • Clobazam, part of the standard of care for epilepsy in Europe, is now FDA-approved for the treatment of seizures in Lennox-Gastaut syndrome [Selmer et al 2009].
  • Phenobarbital, while effective for seizure control, is poorly tolerated because of its effects on cognition.
  • Levetiracetam (Keppra®) has been reported by several families to be ineffective or occasionally associated with an increase in seizure frequency [M Hammer, unpublished data].

Other. When seizures are not responsive to conventional AEDs, the following drugs/treatment modalities may be effective based on anecdotal information:

  • Corticosteroids
  • Immunoglobulins
  • Vagus nerve stimulator
  • Ketogenic diet
  • Cannabinoids

Sleep hygiene. As described for Dravet syndrome, sleep deprivation and illness can exacerbate SCN8A-related seizures; thus, good sleep hygiene should be encouraged. Comorbidity with sleep apnea can also occur frequently in individuals with epilepsy [Malow et al 2000], and can influence seizure control, behavior, and cognition. Polysomnography should be considered if obstructive or central sleep apnea is suspected.

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Surveillance

Evaluate periodically for neurologic, cognitive, and/or behavioral deterioration.

Monitor with EEG and other modalities (e.g., video EEG telemetry or ambulatory EEG) when new or different seizure types are suspected.

Because of the increased risk of SUDEP, some families use oxygen monitoring during sleep.

Agents/Circumstances to Avoid

Several families of affected individuals report worsening of seizures with levetiracetam (Keppra®) [M Hammer, unpublished data].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.