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Aledo-Serrano et al. J Transl Genet Genom 2021;5:443-55 https://dx.doi.org/10.20517/jtgg.2021.40 Page 445

a group of “classical” epileptic encephalopathies, such as West, Lennox-Gastaut, or Dravet syndromes,
which were defined as characteristic electro-clinical syndromes before the etiology was fully understood.
[5]
However, these syndromes are currently undergoing a revisited definition .

The concept of “epileptic encephalopathy”, which the International League Against Epilepsy defines as the
process whereby “epileptic activity and seizures generate cognitive and/or behavioral problems beyond
[11]
those expected for the etiology”, has become obsolete . Substantial clinical data suggest that
neurodevelopmental impairment in classical epileptic encephalopathies start before epilepsy onset and
progress after epilepsy remission. In light of these data, current views of DEEs consider that epileptic
activity in classical epileptic encephalopathies plays only a partial or limited role in the neurodevelopment
of the patient. In those cases, it is established that epilepsy is more an epiphenomenon of the etiological
process (in most cases, genetic), and that it is the abnormal neurodevelopmental trajectory which plays the
leading role in the pathophysiological process. Thus, the concept of “developmental and epileptic
encephalopathies” has emerged, in which it is accepted that neurodevelopmental problems are partly due to
the etiology and partly due to the epileptic process .
[12]
Most classically defined electroclinical syndromes have a poor genotype-phenotype correlation, with
polygenic risk and multiple genes producing the same syndrome (genetic heterogeneity) as well as with
pleiotropic risk alleles - multiple syndromes produced by the same gene (phenotypic heterogeneity). Thus,
syndromes such as West or Lennox-Gastaut are now considered common pathways of expression of
multiple etiologies, so more accurate phenotyping of these patients, beyond the classical triads, will be
essential to reach a diagnosis .
[13]
However, there are other electroclinical syndromes that could be considered successful examples in terms of
genotype-phenotype correlation, such as Dravet syndrome. It is caused by pathogenic variants in SCN1A in
about 85%-90% of cases, showing a haploinsufficiency mechanism. In addition, the diagnosis of Dravet
syndrome has been refined in recent years, as many genes traditionally included in the syndrome, such as
PCDH19 or KCNA2, now have their own specific syndrome, with differential characteristics from classical
Dravet [14,15] . Thus, the redefinition of the concept of epileptic encephalopathies, together with a poorly
genotype-phenotype correlation in the classical electroclinical syndromes, triggered this paradigm shift in
the study of DEEs.

DIFFICULTIES IN GENOTYPE-PHENOTYPE CORRELATION
Phenotypic expansion
As a result of the increased number of patients analyzed with platforms that include a high number of
genes, the phenotypic spectrum related to specific genetic conditions has increasingly expanded. Taking the
SCN1A gene as example, some years ago variants located in this locus were associated with two distinct and
unique phenotypes: Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+). GEFS+ is a
dominantly inherited epilepsy syndrome in which individuals show a predisposition to spontaneous
seizures or seizures triggered by fever and other factors, such as emotional excitement, without refractory
epilepsy or neurodevelopmental disturbances. In contrast, in Dravet syndrome, initial febrile seizures
progress to severe refractory epilepsy after the second or third year, showing neurodevelopmental
problems .
[16]

Currently, clinical findings on SCN1A variants suggest that, in addition to the full spectrum of phenotypes
between GEFS+ and Dravet syndrome, there are also substantially different SCN1A-associated epilepsy
phenotypes that do not fall within the GEFS+/Dravet spectrum . Moreover, SCN1A variants may be
[17]