De novo SCN1A mutations in migrating partial seizures of infancy
D Carranza Rojo1, L Hamiwka, J M McMahon
1Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia.
Insights
Malignant migrating partial seizures of infancy (MPSI) is a severe epileptic encephalopathy. Genetic analysis revealed SCN1A gene mutations or deletions in affected infants, indicating SCN1A as a key gene in MPSI etiology.
Area of Science:
- Genetics
- Neurology
- Pediatrics
Background:
- Malignant migrating partial seizures of infancy (MPSI) is a rare and severe early-onset epileptic encephalopathy.
- The genetic basis of MPSI remains largely unknown, necessitating further investigation.
Purpose of the Study:
- To identify the genetic cause of malignant migrating partial seizures of infancy (MPSI).
Main Methods:
- Genetic screening of 15 unrelated MPSI patients for mutations in known epilepsy genes (SCN1A, CDKL5, STXBP1, PCDH19, POLG).
- Copy number variation analysis using microarray studies.
Main Results:
- A de novo SCN1A missense mutation (p.R862G) was identified in one patient.
- A de novo deletion encompassing SCN1A on chromosome 2q24.2q31.1 was found in another patient.
- Mutations in CDKL5, STXBP1, PCDH19, and POLG were not detected in the majority of patients.
Conclusions:
- SCN1A mutations and deletions are implicated in the etiology of MPSI, representing the most severe phenotype associated with this gene to date.
- While not a frequent cause, SCN1A screening is recommended for patients diagnosed with MPSI.
Objective:
To determine the genetic etiology of the severe early infantile onset syndrome of malignant migrating partial seizures of infancy (MPSI).
Methods:
Fifteen unrelated children with MPSI were screened for mutations in genes associated with infantile epileptic encephalopathies: SCN1A, CDKL5, STXBP1, PCDH19, and POLG. Microarray studies were performed to identify copy number variations.
Results:
One patient had a de novo SCN1A missense mutation p.R862G that affects the voltage sensor segment of SCN1A. A second patient had a de novo 11.06 Mb deletion of chromosome 2q24.2q31.1 encompassing more than 40 genes that included SCN1A. Screening of CDKL5 (13/15 patients), STXBP1 (13/15), PCDH19 (9/11 females), and the 3 common European mutations of POLG (11/15) was negative. Pathogenic copy number variations were not detected in 11/12 cases.
Conclusion:
Epilepsies associated with SCN1A mutations range in severity from febrile seizures to severe epileptic encephalopathies including Dravet syndrome and severe infantile multifocal epilepsy. MPSI is now the most severe SCN1A phenotype described to date. While not a common cause of MPSI, SCN1A screening should now be considered in patients with this devastating epileptic encephalopathy.
