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occasional status epilepticus and severe developmental delay (unpublished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-Mir1 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.
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