Advances in equine juvenile idiopathic epilepsy
by Jenny Alonge
Seizures are relatively uncommon in horses when compared with other species. In equines, seizure activity can be caused by conditions such as septicemia, hypoxic ischemic encephalopathy, metabolic disturbances, including electrolyte imbalances and hypoglycemia, bacterial or viral meningitis, certain medications, liver failure, trauma, and congenital anomalies.
Epilepsy is characterized by recurrent seizures without a precipitating factor, and the International League Against Epilepsy (ILAE) classifies the condition in humans as generalized, localized, and unclassified. Further subdivisions include idiopathic (i.e. primary) and symptomatic (i.e. secondary). Classifying epileptic events is helpful to promote clinical research studies, determine an appropriate treatment protocol, and establish a prognosis.
Although epilepsy is rarely documented in horses, Arabian foals from certain familial lines exhibit a condition known as equine juvenile idiopathic epilepsy (JIE). Recent research has provided new information about this interesting seizure condition.
Equine juvenile idiopathic epilepsy overview
JIE is a hereditary seizure disorder some Arabian foals of Egyptian lineage develop. The condition most often occurs between birth to 6 months of age. An affected foal may experience tonic-clonic seizures that can last as long as five minutes, putting them at risk for secondary complications such as temporary blindness, lethargy, and disorientation. Other more serious complications, such as head injuries and aspiration pneumonia, can also occur. Between seizures, an affected foal exhibits no abnormal signs. Some foals outgrow the condition, but others die or experience lifelong effects. Other JIE factors include:
- Diagnosis — JIE is diagnosed by electroencephalogram (EEG), which measures a foal’s electrical brain activity. Affected foals have characteristic abnormalities in the parietal parasagittal region. Additional clinical and laboratory tests are performed to rule out other potential seizure causes.
- Treatment — Benzodiazepines can be used as a short-term treatment for seizures. The dosage in foals is 0.05 to 0.4 mg/kg, and the dose can be repeated in 30 minutes if necessary. Phenobarbital is usually the drug of choice for long-term seizure management. The recommended loading dose is 12 to 20 mg/kg intravenous (IV) phenobarbital diluted in one liter of saline or dextrose over a 30-minute period, followed by 6 to 12 mg/kg phenobarbital by mouth every 12 hours. Potassium bromide or levetiracetam can also be used in difficult-to-control cases.
- Management — Devices, such as headgear, padded stalls, and deep bedding, should be provided until the seizures are effectively controlled by medication.
- Prevention — To prevent the disorder from perpetuating, affected animals should not be bred.
Investigation of known genetic mutations of Arabian horses in Egyptian foals with juvenile idiopathic epilepsy
JIE is believed to have an autosomal dominant mode of inheritance, but the genetic cause is unknown. One theory postulated that an association exists between JIE and lavender foal syndrome (LFS), but a 2018 University of California (UC) Davis study established that the two conditions are independent syndromes. The UC Davis study details include:
- Hypothesis — Researchers wanted to determine LFS’s carrier status, cerebellar abiotrophy (CA), severe combined immunodeficiency (SCID), and occipitoatlantoaxial malformation (OAAM1) in foals affected by JIE.
- Materials and methods — The researchers tested archived DNA samples for known genetic mutations causing LFS, CA, SCID, and OAAM1. Foals included in the study were diagnosed with JIE based on EEG findings and by ruling out other causes.
- Results — Ten Egyptian Arabian foals were phenotyped as having JIE by EEG. All were negative for genetic mutations that cause LFS, CA, SCID, and OAAM1 except for one foal who was a CA carrier.
- Conclusions — JIE in Egyptian Arabian foals appears to be a phenotypically and genetically distinct disorder from LFS, and no apparent link exists between JIE and CA, SCID, or OAAM1.
TRIM39–RPP21 variants are not associated with juvenile idiopathic epilepsy in Egyptian Arabian horses
A 2019 study investigated whether a 19 base pair deletion, along with a triple-C insertion, in intron 5 of 12 of the Tripartite Motif-Containing 39 Ribonuclease p/mrp 21kDa subunit (TRIM39-RPP21) gene was associated with JIE. In an attempt to confirm this association, researchers genotyped nine EEG-phenotyped JIE-affected foals and nine unaffected foals using Sanger sequencing. They found no significant genotypic or allelic association with the variants and JIE. Researchers concluded that the TRIM39-RPP21 variant is a common variant that happens to be positioned in a highly polymorphic region in the Arabian breed.
Sequence variant in the TRIM39-RPP21 gene readthrough is shared across a cohort of Arabian foals with juvenile idiopathic epilepsy
A 2022 study aimed to identify genetic components shared across a local cohort of Arabian foals with JIE. Researchers conducted whole genome comparisons between nine JIE foals and 27 controls, revealing variants uniquely shared among the nine JIE foals. They also conducted targeted sequencing on these variants to validate their results. Researchers found a single 19bp deletion coupled with a triple-C insertion within the TRIM39-RPP21 gene readthrough the JIE foals shared. Further research is needed to determine if the variant is a credible marker for JIE.
Juvenile idiopathic epilepsy in Arabian horses is not a single-gene disorder
In May 2023, researchers published their findings on whether JIE is a single-gene trait. They conducted a genome-wide association study (GWAS) on 60 JIE cases and 120 genetically matched controls. Researchers identified loci that suggested JIE is not caused by a single locus. Coat color (i.e., chestnut and grey) phenotypes were used as positive control traits to assess the population’s GWAS efficacy. Researchers plan to perform future studies to define candidate regions and explore a polygenic inheritance mode.
Research studies such as these help expand knowledge about JIE to hopefully help find a credible marker for the condition and potentially prevent future cases.
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