Abstract

Objective: To explore the clinical characteristics and genetic variation features  of epilepsy associated with SIK1 gene mutations.  Method: A retrospective summary was conducted on the clinical data and genetic testing result of a child with developmental epileptic encephalopathy caused by SIK1 gene mutation, and literatures about clinical features of epilepsy caused by SIK1 gene mutations were reviewed. Results：The patient, female, with onset at 4 months of age, presented with frequent spasms. Electroencephalogram displayed hypsarrhythmia during interictal period. Gesell assessment showed severe comprehensive developmental delay. The combination therapy of multiple Anti-seizure medications(ASMs) had failed to effectively control epileptic seizures. The clinical-exome sequencing combined Sanger sequencing in proband confirmed a heterozygous missense mutation in SIK1 gene (NM_173354.3: exon14, c.2215A>G/p.Thr739Ala), which was confirmed De Novo mutation, and this mutation site has not been reported yet. A total of 2 English articles were retrieved during literature review, and 8 cases of SIK1 gene mutation in children were reported after merging with the case presented in this article. All cases had epileptic seizures, with onset ages ranging from 20 minutes to 15 months after birth. All children had epileptic seizures, with onset ages ranging from 20 minutes to 15 months after birth. Among them, 4 cases (4/8) were infantile epileptic spasm syndrome, 2 cases (25%) were early myoclonic encephalopathy, 1 case (12.5%) was Otahara syndrome, and 1 case (12.5%) did not reach the diagnosis of epilepsy syndrome and the seizure type is generalized tonic clonic seizures. 7 cases (87.5%) had severe comprehensive developmental delay, and 1 case (12.5%) had normal cognition; 7 cases (87.5%) showed no response to ACTH treatment and failed to combination therapy with multiple ASMs, 1 case（12.5%）epileptic seizures were controlled after monotherapy with sodium valproate; 2 cases died at the age of 3 months and 10 months respectively. All 8 cases were confirmed SIK1 gene mutations through genetic testing, including 5 cases of missense mutations (62.5%) and 3 cases of nonsense mutations (37.5%). Conclusion: SIK1 gene mutations often lead to developmental epileptic encephalopathy, with early-onset refractory epilepsy syndrome as the main clinical phenotype. Treatment with ACTH and various ASMs are ineffective. The De Novo mutation site c.2215A>G/p.Thr739Ala in this case enriches the spectrum of SIK1 gene mutations, providing important evidence for clinical treatment and genetic counseling.