Researchers at the
UC Davis School of Veterinary Medicine have identified the genetic cause of
Equine Juvenile Spinocerebellar Ataxia (EJSCA), a recently recognised and fatal
neurological disease affecting American Quarter Horse foals. The discovery not only
provides breeders with a genetic test to prevent affected foals from being
born, but also advances scientific understanding of neurological disease in
both horses and humans.
EJSCA is an
inherited neurological disorder that affects foals within the first few weeks
of life. Clinical signs typically develop between one and five weeks of age and
progress rapidly. Affected foals initially appear uncoordinated and exhibit
proprioceptive ataxia, meaning they have difficulty determining the position of
their limbs in space. Within days, many develop severe weakness of the hind
limbs, become unable to stand without assistance, and eventually require
euthanasia on welfare grounds.
The disease results
from degeneration of axons, the long nerve fibres that connect neurons and
allow communication between the brain, spinal cord and limbs. As these pathways
deteriorate, the nervous system can no longer accurately transmit information about
movement and body position. Consequently, affected foals lose balance and
coordination despite appearing normal at birth.
The first
recognised case of EJSCA was identified in 2020 in a Quarter Horse filly known
as “Curly Sue.” Veterinarians initially suspected another neurological
condition, equine neuroaxonal dystrophy (eNAD), but further investigations
revealed that the foal was suffering from a previously unrecognised disease.
To identify the
genetic cause, researchers at UCDavis performed whole-genome sequencing on
seven affected foals and compared their DNA with that of unaffected relatives
and unrelated control horses. The investigation identified an 82-kilobase
region on chromosome 11 that contained several candidate genetic variants.
Further molecular studies demonstrated that the causative mutation was located
within a non-coding region of the ferredoxin reductase (FDXR) gene.
Unlike many
disease-causing mutations that alter the protein-coding sequence of a gene,
this mutation affects how the gene is processed into messenger RNA. The variant
causes the insertion of a cryptic exon - a segment of genetic material that is
not normally included in the final RNA transcript. As a result, affected foals
produce lower amounts of functional FDXR protein.
This finding is
significant because FDXR plays an important role in cellular energy metabolism
and nervous system function. Analysis of spinal cord and liver tissues showed
that affected foals had substantially reduced FDXR protein concentrations
compared with healthy controls. Importantly, mutations in the human FDXR gene
are known to cause neurological disease, making EJSCA a potentially valuable
natural model for studying similar disorders in people.
The researchers
determined that EJSCA follows an autosomal recessive pattern of inheritance.
This means that affected foals inherit two copies of the mutation, one from
each parent. Horses carrying only one copy remain clinically normal but can
pass the variant to their offspring. When two carrier horses are bred together,
there is a 25% chance of producing an affected foal.
Screening of more
than 1,000 Quarter Horses identified 25 carriers, indicating that the mutation
currently occurs at a relatively low frequency within the breed. It has not yet
been detected in other horse breeds. Because all known affected foals trace back
to a single influential sire, researchers believe the mutation may have arisen
relatively recently.
The development of
a genetic test by the UC Davis Veterinary Genetics Laboratory now allows
breeders to identify carrier animals before breeding. By avoiding
carrier-to-carrier matings, breeders can effectively prevent the birth of
affected foals while maintaining valuable bloodlines. This discovery represents
the first non-coding neurological genetic variant identified in horses and the
first known genetic cause of a degenerative axonal disease in the species,
marking an important milestone in equine genetics and neurological research.
For more details,
see:
Brown, B. N., Dahlgren, A. R., Ghosh, S., Durbin-Johnson, B.,
Willis, A., Olivas, C., York, D., Grahn, R., Bellone, R. R., Cortopassi, G. A.,
Miller, A. D., Brown, C. T., Woolard, K., & Finno, C. J. (2026).
An intronic variant in Ferredoxin Reductase (FDXR) creates a
cryptic exon in Quarter Horses with Equine Juvenile Spinocerebellar Ataxia.
PLoS genetics, (2026).
22(5), e1012158.
https://doi.org/10.1371/journal.pgen.1012158