Narrowing down the minimal critical region for epilepsy susceptibility in chromosome 5p

Aims:

Patients with duplication 5p often present epilepsies (7/18 reported cases). Since most of these duplications are large, little is known about the critical region for epilepsy susceptibility. Here, we report two patients with epilepsy and a microduplication 5p13.1. This might help to narrow down the minimal critical region for epilepsy susceptibility on chromosome 5.

Patients:

Both patients developed pharmacoresistant epilepsies at the age of 2.5 years and showed global developmental delay. MRI was normal. The epilepsy was classified in patient 1 as a generalized epilepsy with typical absences, photosensitivity and generalized spike-wave discharges, in patient 2 as an idiopathic (=non-lesional) epilepsy with atypical absences and pseudofoci in the EEG.

Results:

Array-CGH analysis revealed small duplications (6.41 Mb, patient 1 and 0.76Mb, patient 2) in the short arm of chromosome 5 (5p12 to 5p13.1, patient 1 and 5p13.1, patient 2).

Conclusion: The overlapping region in band 5p13.1 comprises only four genes (RICTOR, FYB, C9 and DAB2), which therefore may be candidate genes for epilepsy susceptibility in 5p duplications. Among these, the most interesting gene is FYB (OMIM 602731): FYB codes for a binding protein, which binds a protein-tyrosine kinase oncogene (=FYN). FYN plays a role in signaling pathways including axon guidance. In an electrical kindling model in mice it was shown that null mutations of the FYN gene lead to a striking retardation in the rate of kindling. To date, only few case reports of FYB gene mutations have been reported. However, as it codes for a FYN-binding protein it could be postulated that a duplication of FYB could shift the interaction between FYB and FYN, thereby leading to an altered seizure threshold in patients with a duplication of FYB.

Duplication 5p - FYN - FYB - epilepsy