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Clinical characteristics

SCN2A-related disorders with epilepsy
SCN2A-related epilepsy phenotypes vary in age of seizure onset, types of seizures, response to medications and seizure outcomes. Phenotypes with epilepsy onset in neonatal/early-infancy, mid-late infancy, and childhood are recognised. The broad spectrum of severity is most evident with neonatal-early-infancy seizure onset, where ‘benign’, intermediate and severe epilepsy phenotypes are recognised.

Benign familial neonatal-infantile seizures (BFNIS) is an age-limited epilepsy with seizure onset typically between the ages of 0-4 months (although onset as late as 23 months is reported). There may be variability in age of seizure onset within a family. Seizures are focal, with variable semiology, most commonly with motor features, and varying in frequency from a few seizures only to clusters of seizures occurring on a daily basis. Seizures are usually treatment-responsive, remit by approximately age 12 months and usually do not recur. Development and intellectual function are typically normal. Most affected individuals have no other neurologic symptoms, although episodic ataxia beginning in childhood has been reported.

Severe neonatal/early-infantile phenotype, also known as ‘early-onset Developmental and Epileptic Encephalopathy (DEE)’, is associated with the onset of focal seizures before the age of 3 months, most commonly in the first week of life. Seizures are usually brief, but extremely frequent (usually multiple daily or multiple hourly). The interictal electroencephalogram (EEG) is typically highly abnormal; background abnormalities including burst-suppression may be seen, and multifocal epileptiform discharges are frequent. The electroclinical phenotype is often consistent with early infantile epileptic encephalopathy (Ohtahara syndrome) or epilepsy of infancy with migrating focal seizures (EIMFS); in fact, SCN2A is one of the most common causes of these epileptic syndromes. Seizures can be very difficult to treat although they may respond to sodium channel blocking antiepileptic drugs (SCBs), particularly phenytoin (PHT) (see the Professionals – Management section). Additional seizure types may occur, including infantile spasms, myoclonic, myoclonic-tonic and tonic seizures, usually beginning after the early infantile period. Seizures continue to into childhood in most individuals, although may reduce in frequency from around age 2-4 years.

Development is abnormal from birth or shortly after seizure onset. Difficulty in visual fixing and following is usually present in early infancy. Developmental regression occurs in some individuals at seizure onset, evolution or exacerbation. Most individuals have DD/ID in the long-term, ranging in severity from moderate to profound. Although SCBs may improve seizures, medication does not appear to significantly improve developmental outcomes.

Movement disorders are often present in the neonatal/early infantile period, and may be severe. It can be difficult to determine which abnormal movements are epileptic and which not; video-EEG recordings of episodes may be required. Movement disorders are often polymorphic, and often include dystonia, non-epileptic myoclonus and excess startle.

Other clinical features reported in some individuals include acquired microcephaly, abnormalities of tone (hypotonia and hypertonia reported), and paroxysmal episodes including episodic hemiparesis and ataxia. Gastrointestinal problems such as constipation and reflux are common and can be severe, but other non-neurologic features are rare. A variety of non-specific brain imaging features are reported, but neuroimaging may also be normal.

Intermediate neonatal/early-infantile phenotype has a similar electroclinical phenotype in the neonatal and early-infantile period to the severe phenotype, with treatment-resistant focal seizures. ‘Severe’ epileptic syndromes such as EIMFS are reported. However, the clinical features are milder in the longer term; developmental outcomes can range from normal to moderately impaired, evolution to other seizures types such as infantile spasms is typically not seen, and seizures may remit or become less frequent and/or less pharmacoresistant beyond the first year of life. Other features may include ASD, relatively mild movement disorders such as stereotypies, non-epileptic paroxysmal episodes including episodic ataxia and hemiparesis, and gastrointestinal symptoms, although some individuals have none of these features.

Given the similar initial presentation to the more severe phenotype, factors present in infancy that predict the more intermediate phenotype are important to understand. These favourable prognostic factors are not yet well-defined, but may include better visual attention and an inter-ictal EEG showing normal background organisation.

Mid-late infancy-onset phenotype, also known as ‘later-onset DEE’, has onset of seizures between the ages of 3-15 months. In most individuals, seizures are not the initial symptom. Development may be delayed prior to seizure onset, and movement disorders, severe vomiting and failure to thrive, and irritability may occur in early infancy.

The presenting seizure type is infantile spasms (and/or tonic seizures), usually consistent with West syndrome (infantile spasms + hypsarrhythmia). Although spasms may be (at least transiently) responsive to treatment (see below), seizures (usually generalised seizure types such as tonic seizures, spasms and myoclonic seizures) usually continue into childhood, although may reduce in frequency from around age 2-4 years. The effect of SCBs is not well understood – both seizure exacerbation and improvement are reported.

Developmental regression may occur at epilepsy onset, and in the long-term, most individuals have moderate-severe DD/ID. ASD may be present. Movement disorders, particularly choreoathetosis, may be present. Other reported features include abnormalities of tone, acquired microcephaly, episodic agitation with red, hot areas of the body, and gastrointestinal symptoms. MRI brain imaging may be normal, or may show non-specific abnormalities.

Childhood-onset phenotype has seizure onset in or after the second year of life (onset as late as age 17 years is reported). The electroclinical phenotype is not well-understood; a range of seizure types and epileptic syndromes, treatment responses and seizure outcomes are reported.

Development may be normal or abnormal prior to epilepsy onset. Approximately one-third of individuals whose initial presentation is with DD/ID or ASD develop epilepsy in childhood. Regression may occur at epilepsy onset. In the long-term, most individuals have DD/ID or an ASD.

SCN2A-related disorders in which seizures may be absent
Intellectual disability and/or autism may occur without epilepsy, with a broad spectrum of severity. Some individuals have a period of developmental regression. Other clinical features may include hypotonia and gastrointestinal symptoms.

Episodic ataxia (EA) begins between the ages of 10 months and 14 years. The duration of episodes varies from minutes to several hours in most individuals, although episodes lasting weeks are reported. The frequency of episodes is highly variable, ranging from daily to less than yearly; there is some suggestion that episodes are longer in those in whom they are less frequent. Potential triggers include minor head trauma and fatigue. No treatment has been demonstrated to be consistently effective. Some individuals have had benefit from carbamazepine or acetazolamide, but others had no improvement. Approximately 80% of individuals have normal development or mild DD/ID.

While EAcan occur without epilepsy, many individuals do have seizures (as noted above). Seizures usually have onset before age three months, and may be responsive to SCBs. Some individuals are able to cease AEDs, but many require long-term treatment.