DO: 0081424;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2q24.3 | Epilepsy, familial focal, with variable foci 4 | 617935 | Autosomal dominant | 3 | SCN3A | 182391 |
A number sign (#) is used with this entry because of evidence that familial focal epilepsy with variable foci-4 (FFEVF4) is caused by heterozygous mutation in the SCN3A gene (182391) on chromosome 2q24.
Heterozygous mutation in the SCN3A gene can also cause developmental and epileptic encephalopathy-62 (DEE62; 617938), a more severe epileptic disorder.
Familial focal epilepsy with variable foci-4 (FFEVF4) is an autosomal dominant seizure disorder characterized by onset of focal seizures in the first years of life. Some patients may have secondary generalization and/or mild developmental deficits (summary by Vanoye et al., 2014).
For a discussion of genetic heterogeneity of FFEVF, see FFEVF1 (604364).
Vanoye et al. (2014) reported 4 unrelated children with early-onset focal seizures. One patient had onset of seizures in the neonatal period, 2 had onset between 16 and 22 months, and the fourth patient had onset at age 5 years. The seizures were well controlled, and all were able to discontinue medication later in childhood. Two patients had mild cognitive impairment, including speech delay, attention deficit-hyperactivity, and learning disabilities, but the other 2 patients had normal development. Brain imaging was normal in 2 patients and showed nonspecific minor abnormalities in the other 2 patients. Three patients had a family history of epilepsy, but affected family members were not available for study.
Lamar et al. (2017) reported a 2-year-old girl with global developmental delay, hypotonia, microcephaly, and onset of focal seizures in the first week of life. She also had autonomic dysfunction, including skin flushing and sweating associated with pupil dilation and ptosis. She was unable to walk, had delayed speech, and poor overall growth.
Celle et al. (2013) reported a 3-year-old boy with delayed psychomotor development, autistic features, severe language delay, and microcephaly associated with a 291-kb interstitial deletion at chromosome 2q24.3 including both the SCN2A (182390) and SCN3A genes. The patient did not have seizures. Parental DNA was not available for study.
The transmission pattern of FFEVF4 in the patients reported by Vanoye et al. (2014) was consistent with autosomal dominant inheritance.
In 4 unrelated patients with FFEVF4, Vanoye et al. (2014) identified 4 different heterozygous missense mutations in the SCN3A gene (see, e.g., 182391.0001-182391.0003). The mutations were found by genetic screening of the SCN3A gene in 179 pediatric patients with focal epilepsy who were negative for mutations in the SCN1A gene. No family members were available for study, so analysis of inheritance pattern and/or segregation was not possible. In vitro functional expression studies showed that the mutations caused variable defects of channel function, with only some of the mutations altering the activation and/or inactivation kinetics. However, all the mutations resulted in increased inward currents during a slow depolarizing voltage ramp, indicating channel dysfunction capable of enhancing the response to subthreshold depolarizing inputs and promoting hyperexcitable networks. Zaman et al. (2018) noted that all the variants identified by Vanoye et al. (2014) were found at a low frequency in the ExAC database and may either result in subtle changes in channel function or may act as risk alleles.
In an 2-year-old girl with FFEVF4, Lamar et al. (2017) identified a de novo heterozygous missense mutation in the SCN3A gene (L247P; 182391.0004). The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies showed that the mutant channel had no detectable sodium current resulting from a significant reduction of mutant SCN3A at the cell surface, suggesting that the mutation caused a trafficking defect. Fewer channels at the cell surface would be predicted to reduce the magnitude of the inward current, which may contribute to disease pathogenesis. The findings were consistent with a loss-of-function effect.
Lamar et al. (2017) found that heterozygous Scn3a +/- mice had decreased Scn3a mRNA and protein levels in the brain compared to wildtype. Mutant mice had increased susceptibility to induced seizures, but did not exhibit spontaneous seizures. Heterozygous mice also showed deficits in locomotor activity and motor learning. Some of the mutant mice showed focal cortical abnormalities, including disruptions in cortical lamination and invaginations.
Celle, M. E., Cuoco, C., Porta, S., Gimelli, G., Tassano, E. Interstitial 2q24.3 deletion including SCN2A and SCN3A genes in a patient with autistic features, psychomotor delay, microcephaly and no history of seizures. Gene 532: 294-296, 2013. [PubMed: 24080482] [Full Text: https://doi.org/10.1016/j.gene.2013.09.073]
Lamar, T., Vanoye, C. G., Calhoun, J., Wong, J. C., Dutton, S. B. B., Jorge, B. S., Velinov, M., Escayg, A., Kearney, J. A. SCN3A deficiency associated with increased seizure susceptibility. Neurobiol. Dis. 102: 38-48, 2017. [PubMed: 28235671] [Full Text: https://doi.org/10.1016/j.nbd.2017.02.006]
Vanoye, C. G., Gurnett, C. A., Holland, K. D., George, A. L., Jr., Kearney, J. A. Novel SCN3A variants associated with focal epilepsy in children. Neurobiol. Dis. 62: 313-322, 2014. [PubMed: 24157691] [Full Text: https://doi.org/10.1016/j.nbd.2013.10.015]
Zaman, T., Helbig, I., Babic Bozovic, I., DeBrosse, S. D., Bergqvist, A. C., Wallis, K., Medne, L., Maver, A., Peterlin, B., Helbig, K. L., Zhang, X., Goldberg, E. M. Mutations in SCN3A cause early infantile epileptic encephalopathy. Ann. Neurol. 83: 703-717, 2018. Note: Erratum: Ann. Neurol. 85: 948 only, 2019. [PubMed: 29466837] [Full Text: https://doi.org/10.1002/ana.25188]