Significance of the SCN1A p.R1928G Change in Severe Myoclonic Epilepsy of Infancy
Zucca et al. report 12 novel mutations in the SCN1A gene, 2 of which, c.5782C>G and c.3620T>C, were
detected in a single patient affected with severe myoclonic epilepsy of infancy (Dravet syndrome).(1) The
finding of 2 unrelated pathogenic mutations in the same gene is intriguing in a disease with autosomal
dominant inheritance, where isolated point mutations or larger microdeletions are usually associated with a
haploinsufficiency phenotype. The authors wisely point out that they cannot exclude 1 of the changes being a
rare variant.
Interestingly, while screening a similar group of children with infantile epileptic syndromes for mutations in
SCN1A, we detected the c.5782C>G change in 2 patients with neonatal-onset epileptic encephalopathy,
featuring a mixed seizure disorder punctuated by occasional status epilepticus and severe developmental
delay (unpublished data). Of note, the c.5782C>G change, leading to a p.R1928G amino acid substitution,
has also been described as a rare variant, present in 1.7% of 60 control individuals,(2) and hence we
considered it an unlikely disease-causing mutation in our 2 patients. In addition, we further confirmed the
presence of the change in 1 out of 200 chromosomes from the Spanish general population, but not in 100
chromosomes of selected non-epileptic individuals. Despite the conservation of the residue in mammalian
orthologs, the observed change is present in evolutionarily lower organisms and in the human paralog
SCN8A, raising the issue of a possible modulatory effect of the variant on the biophysical properties of the
channel.
However, a more compelling evidence of the lack of functional relevance of the p.R1928G change comes
from its identification in a family with different forms of migraine, including hemiplegic migraine in the
index case, where the variant segregated poorly with the phenotype.(3) The authors conclusively showed that
cells expressing the variant equivalent to the p.R1928G change in the highly homologous SCN5A subunit
displayed normal biophysical properties.
Daniel Carranza M.D., Amalia Martínez-Mir Ph.D. and Alfons Macaya M.D. (Grup de Recerca en
Neurologia Infantil, Hospital Universitari Vall d’Hebron, Barcelona, Spain, and Departamento de
Bioquímica Médica y Biologia Molecular, Facultad de Medicina, Universidad de Sevilla, Sevilla, Spain)
No relevant conflicts of interest
References
1. Zucca C, Redaelli F, Epifanio R, et al. Cryptogenic Epileptic Syndromes Related to SCN1A. Twelve
Novel Mutations Identified. Arch Neurol.2008;65(4):489-494.
2. Wallace RH, Scheffer IE, Barnett S, et al. Neuronal sodium -channel alpha1-subunit mutations in
generalized epilepsy with febrile seizures plus. Am J Hum Genet.2001;68(4):859-65.
3. de Vries B, Freilinger T, Vanmolkot KR, et al. Systematic analysis of three FHM genes in 39 sporadic
patients with hemiplegic migraine. Neurology.2007;69(23):2170-2176.