NDUFS7 variant in dogs with Leigh syndrome and its functional validation in a Drosophila melanogaster model.

Two Jack-Russell Terrier × Chihuahua mixed-breed littermates with Leigh syndrome were investigated. The dogs presented with progressive ataxia, dystonia, and increased lactate levels. Brain MRI showed characteristic bilateral symmetrical T2 hyperintense lesions, histologically representing encephalomalacia. Muscle histopathology revealed accumulation of mitochondria. Whole genome sequencing identified a missense variant in a gene associated with human Leigh syndrome, NDUFS7:c.535G > A or p.(Val179Met). The genotypes at the variant co-segregated with the phenotype in the investigated litter as expected for a monogenic autosomal recessive mode of inheritance. We investigated the functional consequences of the missense variant in a Drosophila melanogaster model by expressing recombinant wildtype or mutant canine NDUFS7 in a ubiquitous knockdown model of the fly ortholog ND-20. Neither of the investigated overexpression lines completely rescued the lethality upon knockdown of the endogenous ND-20. However, a partial rescue was found upon overexpression of wildtype NDUFS7, where pupal lethality was moved to later developmental stages, which was not seen upon canine mutant overexpression, thus providing additional evidence for the pathogenicity of the identified variant. Our results show the potential of the fruit fly as a model for canine disease allele validation and establish NDUFS7:p.(Val179Met) as causative variant for the investigated canine Leigh syndrome.

Levetiracetam-responsive paroxysmal exertional dyskinesia in a Welsh Terrier.

A 5-and-a-half-year old, 9-kg, spayed, female Welsh Terrier presented with a 12 month history of paroxysmal exertion-induced dyskinesia (PED) characterized by recurrent episodes of involuntary hyperkinetic movements, abnormal muscle tone, and contractions triggered by exercise. A single episode occurred within 2 hours after exercise, lasted from 7 to 10 minutes, and resolved without treatment. The owner sought treatment for the dog when the episodes began to last longer (20-30 minutes), and occurred as long as 2.5 to 8 hours after exercise. Diazepam administered intranasally at the start of an episode promptly alleviated the symptoms. Maintenance therapy with levetiracetam proved effective, such that the dog was gradually returned to exercise. However, attempts to wean the dog off the drug resulted in reoccurrence. Although the pathophysiology of PED is not fully understood, the clinical presentation and the positive response to antiepileptic therapy highlight the overlap between disease pathways in epilepsy and PED in dogs.

The effect of the combination of locking screws and non-locking screws on the torsional properties of a locking-plate construct.

Little is known about the torsional properties of bone-plate constructs when a combination of locking and non-locking screws have been used. Sixty cadaveric canine femurs were divided into three groups. In the first group, the plate was affixed using three non-locking screws. In the second group, only locking screws were used while a combination of one locking and two non-locking screws were used in the third group. All constructs were subjected to torsion until failure. Torque, angle of torsion, and work were all calculated at the maximum failure point, as well as at five degrees of plastic deformation, which was thought to be more representative of clinical failure. At the maximum failure point, the locking group had significantly higher torque, angle, and work values than the non-locking group. The combination group was intermediate to the two other groups, and significantly differed from the non-locking group in torque, and from the locking group in work. At five degrees of plastic deformation, the locking group required significantly higher torque and work than the non-locking group. The combination group required a significantly higher torque than the non-locking group. This study suggests that a construct composed of all locking screws will fail at a greater torque value, and sustain greater work to failure in torsion compared to a construct composed of all non-locking screws. The addition of a single locking screw to an otherwise non-locking construct will increase the torque at the offset failure point and may be of clinical value in constructs subjected to high torsional loads.