Categories: Behaviour / neurological phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608301 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant with incomplete penetrance

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2011

Cross-species summary: Renamed from 'Epilepsy, benign familial juvenile' to 'Epilepsy, benign familial juvenile, LGI2-related' [11/06/2024]

Species-specific name: Benign familial juvenile epilepsy; remitting focal epilepsy; benign juvenile epilepsy syndrome; juvenile epilepsy

Species-specific symbol: BFJE

Inheritance: Seppälä et al. (2011): "BFJE is transmitted in imperfect Mendelian fashion. In the vast majority of cases, 93%, homozygous mutation is required for the disease to manifest. In a minority, 7%, heterozygosity suffices. Conversely, 1.8% of dogs may be resistant to seizing despite homozygous mutation. Finally, we found no dog with homozygous wt genotype at Lgi2 c.1552 that has BFJE."

Mapping: By conducting a GWAS on 11 discordant sib-pairs (7 full-sibs and 4 half-sibs) of the Lagotto romagnolo breed, each genotyped with the Affymetrix's Canine SNP Array version 1 (yielding 17,273 informative SNPs for analysis), Seppälä et al. (2011) mapped this disorder to a region on chromosome CFA3. Subsequent homozygosity mapping narrowed the region to 1.7Mb between 87.3 and 89.0Mb, which contains 9 genes.

Molecular basis: By sequencing the most likely of 9 positional candidate genes (see Mapping section), Seppälä et al. (2011), part of the LUPA consortium, discovered that this type of epilepsy in the Lagotto romagnolo breed is due to a nonsense mutation (c.1552A>T (p.K518X)) in the gene for LGI2. Noting that mutations in this gene have not yet been reported to be causative of epilepsy in humans, but that mutations in a "sister" gene, LGI1, result in lateral temporal lobe epilepsy in humans, the authors go to considerable lengths to describe how this discovery in dogs may well inform future studies of the genetic basis of epilepsy in humans.

Clinical features: BFJE is characterised by juvenile-onset seizures beginning at five to nine weeks of age and typically spontaneously remit by thirteen weeks of age (Jokinen et al., 2007). Affected puppies exhibit generalised tremor, ataxia and stiffness during seizures and severe cases show neurological signs such as ataxia and hypermetria between epileptic episodes (Jokinen et al., 2007). Seizures can occur at any time of the day and the puppy may or may not be conscious during the episode (Jokinen et al., 2007). Following remission, BFJE-affected puppies often show behavioural abnormalities in adulthood, including increased inattention and excitability (Jokinen et al., 2015). On rare occasions, the patient may experience seizures years after remission, or develop progressive neurological disorders that eventually require euthanasia (Jokinen et al., 2015). BFJE puppies show epileptiform activity on electroencephalogram, both during and in between epileptic episodes. IT thanks DVM student Tina Gong, who provided the basis of this contribution in May 2023.

Pathology: Affected dogs have a relatively small cerebellum and intracytoplasmic inclusion bodies in cerebellar Purkinje cells (Jokinen et al., 2007). IT thanks DVM student Tina Gong, who provided the basis of this contribution in May 2023.

Breed: Lagotto Romagnolo (Dog) (VBO_0200804).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: