Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

Abstract

Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN8A-DEE is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic-clonic manifestations. Spasm-like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEGs) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild-tomoderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN8A-DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN8A-related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN8A-DEEs occur de novo.

Cognitive performance and behavior across idiopathic/genetic epilepsies in children and adolescents

“…Our IQ results align with a study which tested epilepsies in general, which were difficult to treat, like most of our GEs 19 . In our study, the rate of impairment is lower than in studies focusing on syndromes or mutations related to DEEs 31 , 32 . A possible reason for this may be the heterogeneity of our GE cohort.…”

Biological concepts in human sodium channel epilepsies and their relevance in clinical practice

“…We identified epilepsy patients carrying single nucleotide variants affecting SCN1A/2A/8A from two sites: Danish Epilepsy Center Filadelfia (Dianalund, Denmark), including case series by Møller et al, Wolff et al, and Gardella and Møller and unpublished cases (Table ); and Royal Hospital for Children (Glasgow, UK), including case series by Zuberi et al and unpublished cases (Table ). Diagnostic criteria have been published previously .…”

“…51 This SCN2A/8A coexpression might offer a reciprocal rescue mechanism for both SCN2A and SCN8A variants and is clinically reflected in the good response of both epilepsies to SCBs, particularly for those presenting with early onset GoF. 15,30 Taken together, the correlated expression profiles and phenotypic similarities suggest that Na V 1.2 and Na V 1.6 appear to compensate partially upon the disruption in either SCN2A or SCN8A function.…”

Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse*

“…2,[4][5][6] Increased early mortality is a feature of the syndrome. 7 We previously generated two mouse models of SCN8A encephalopathy expressing patient variants, a constitutive knockin of the variant p.Asn1768Asp (N1768D) 8 and a conditional knockin of the variant p.Arg1872Trp (R1872W). 9,10 N1768D, the first identified mutant channel in this disorder, causes impaired channel inactivation and neuronal hyperactivity.…”