Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 54

An increased prevalence of epilepsy has been described for many dog breeds (Jaggy et al., 1998; Kathmann et al., 1999; Berendt et al., 2002, 200; Casal et al., 2006; Gullov et al., 2011), which raises the possibility of genetic risk factors also being responsible for drug-responsiveness. The Lagotto Romagnolo, as aforementioned, has a benign childhood or juvenile epilepsy, which goes into remission in many affected dogs with age, as the function of the Lgi2 gene in cerebral synaptic remodelling becomes less important (Jokinen et al., 2007; Seppala et al., 2011). The Lgi2 gene is involved in the immediate post-natal phase of neuronal pruning, but then the Lgi1 gene has a more important role in the regulation of the later part of pruning.

Another gene mutation that has been associated with improved seizure control is located on the ABCB1 gene. The ABCB1 (multidrug resistance (MDR) 1) gene encodes a transmembrane protein, the permeabilityglycoprotein (P-gp). P-gp, an ATP-dependent multidrug transporter, expressed at the blood–brain barrier (BBB), protects the brain from potential central nervous system (CNS) toxins (Schinkel et al., 1994, 1996; Schrickx and Fink-Gremmels, 2008), including AEDs such as PB (Potschka et al., 2002; Basic et al., 2008). Dysfunction of this neuro-protective BBB efflux pump can lead to BBB dysfunction and consequently CNS intoxication (Schinkel et al., 1994, 1996). Collies and other herding breeds can be affected by such a dysfunction of the P-gp transporter caused by a four base-pair deletion (c.296_ 299del) in exon 4 of the ABCB1 gene (Mealey et al., 2001). A homozygous deletion in this region cannot only lead to CNS intoxication by drugs such as ivermectin, but also has been suggested to improve medical seizure control in affected collies (Muñana et al., 2012a).

Border collies are, however, known to have an aggressive seizure phenotype characterized by high seizure frequency, cluster seizures and poor drug responsiveness. In a recent study, 71% of Border collies were classified as pharmacoresistant (Hülsmeyer et al., 2010). PB-resistant epileptic Border collies had a single nucleotide polymorphism (SNP) at intron 1 near the 5-end of the ABCB1 gene, which could influence the promoter elements of this gene (Alves et al., 2011). A polymorphism at the promoter region could influence transcription activity and therefore might increase the level of P-gp expression at the BBB. The same group looked at another breed, the Australian shepherd dog, which is closely related to the Border collie and also has a severe epilepsy phenotype (Weissl et al., 2012). In this dog breed, they were not able to identify a polymorphism related to drug-refractoriness.

Another recent study looked at gene differences between PB responders and non-responders (Kennerly et al., 2009). Five genes were suggested to have an association with PB response, although they did not reach statistical significance after adjustment for multiple comparisons (KCNQ3, SCN2A, GABRA2, EPOX HYD and ABCB4). Three of these genes encode ion channels (KCNQ3, voltage gated potassium ion channel important for post-excitatory membrane re-polarization; SCN2A, sodium ion channel; GABRA2, GABA receptor), all of them are AED targets (Armijo et al., 2005). The other two genes are involved in PB metabolism (EPOX HYD) or transportation (ABCB4) (Kennerly et al., 2009).