Our patient fulfilled the criteria for BECTS variant as aforementioned and had a heterozygous RELN mutation predicted to be disease-causing. Recently, remarkable progress in unraveling genetic ethology of BECTS or Rolandic epilepsy has been achieved with more than ten susceptible genes spotted to be linked with the syndrome, including GRIN2A, ELP4, SRPX2, BDNF, KCNQ2, KCNQ3, DEPDC5, RBFOX, GABRG2, PRRT2 and so on[9-11]. However, these identified genes do not account for all known cases and more research is required for exploring this possible multi-gene disease. We report a case with RELN mutation that may expand the known disease-relating gene group of BECTS. RELN gene encodes a protein called reelin that regulates the correct formation of laminated structures during embryonic development and modulates dendritic growth and synaptic plasticity at postnatal and adult stages [12]. Homozygous RELN mutations[13] were reported to cause lissencephaly and cerebellar hypoplasia while a series of heterozygous mutations(c.2392C>A, c.2531C>T,c.8347G>T, c.2288A>G, c.2168A>G, c.9526G>A, c.2015C>T) were found in Autosomal-Dominant Lateral Temporal Epilepsy[14].With regard to BECTS or Rolandic epilepsy, the RELN gene mutation(c.9976C>T, p.Arg3326Ter) was once reported in the Clinvar database and classified as pathogenic. Additionally, Dr Judith Conroy [3]established a cohort of Landau-Kleffner syndrome with two discordant monozygotic twin pairs and 11 isolated cases, discovering a number of candidate genes including RELN mutations(c.7438G>A, c.5284G>A). The study of LKS, BECTS and CSWS suggested that the disease spectrum may share the common genetic basis[15].Therefore we speculate that RELN gene may be a candidate gene for this disease, and certainly more study is needed to prove the assumption.
In our case, the patient responded well to the methylprednisolone pulse therapy. Several other studies have also confirmed the efficacy of corticosteroids in treating refractory epilepsy, especially in cases with ESES (including BECTS variant, LKS and CSWS). The responder-rate (seizure frequency reduce >50%) vary between 59% and 85%, while the relapse rate is ranging from 0 to 51% within 6-12 months[6, 16-19]. Luckily, no relapse has occurred in our case over the 1-year follow-up. The mechanism of corticosteroids therapy for epilepsy may be as follows: promotes brain maturation; directly acts on central nervous system receptors to increase cerebrospinal fluid-GABA levels; performs anti-inflammation, immune regulation and immunosuppression [6].
The gene mutation of ELP4 and SRPX2 have been identified in the ESES related diseases[20, 21], and discovered to play an important role in cell proliferation, motility, migration, and adhesion[11, 22, 23]. Coincidentally, the RELN gene is also related to the development of the central nervous system, which includes neuron migration, proper formation of cortical layers, and synaptogenesis [24]. Corticosteroids therapy can help myelin and dendrite formation as well as assisting brain maturation, thereby to compensate the effects caused by the gene mutation[25]. Moreover, another common genetic mutation GRIN2A in this disease spectrum, encoding glutamate receptor, N-methyl-D-aspartate (NMDA), implies that BECTS may have other pathogenic mechanisms like NMDA receptor abnormalities[26, 27]. It has been showed that seizures can be induced by upregulating NMDA receptors on post-synaptic cells via an activation of the GluN2B subunit of the NMDA receptor [28].Once significant mutations occur to the RELN gene, the blocking of reelin protein will increase the concentration of GluN2B –NMDA[29], so as to trigger the seizure. Fainberg [30] once reported a patient with LKS and GRIN2A mutation, who was responsive to immunotherapy, suggesting that autoimmune mechanism could be a component of the underlying disease-causing factors. So this maybe another reason why our patient with RELN mutation was responsive to corticosteroids therapy.
We report a case of BECTS variant with RELN gene mutation successfully treated by methylprednisolone pulse therapy. The underlying causes of the BECTS variant could be the brain immaturity caused by gene mutation and immune factors, both of which are responsive to corticosteroids therapy. Undoubtedly, further studies and more cases are needed for confirmation.