A knockout mutation associated with juvenile paroxysmal dyskinesia in Markiesje dogs indicates SOD1 pleiotropy

Abstract

A juvenile form of paroxysmal dyskinesia segregated in the Markiesje dog breed. Affected pups exhibited clinical signs of a severe tetraparesis, dystonia, cramping and falling over when trying to walk. In most cases, the presentation deteriorated within weeks and elective euthanasia was performed. Pedigree analysis indicated autosomal recessive inheritance. Genome-wide association and homozygosity mapping of 5 affected dogs from 3 litters identified the associated locus on chromosome 31 in the region of SOD1. The DNA sequence analysis of SOD1 showed that the patients were homozygous for a frameshift mutation in the fourth codon. None of the other analyzed dogs of the breed was homozygous for the mutation, indicating full penetrance of the genetic defect. Mutations in SOD1 are known to cause recessive degenerative myelopathy in middle-aged dogs with low penetrance and dominant amyotrophic lateral sclerosis in humans with variable age of onset. Our findings are similar to recent observations in human patients that a loss of function mutation in SOD1 leads to a juvenile neurologic disease distinct from amyotrophic lateral sclerosis.

The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1

“… 25 In addition to this new human case, a truncating homozygous loss-of-function mutation in SOD1 was recently identified in Markiesje dogs that exhibited progressive tetraparesis and muscle wasting, in addition to brainstem and spinal cord atrophy. 63 However, it is notable that Sod1 knockout mice do not replicate the severe motor neuron phenotype that develops in humans despite developing a significant, motor neuropathy in later life in addition to visceral symptoms such as liver tumours, sarcopenia, and ocular symptoms. 56 , 64–66 Given the relatively young age of the patients described here, later-onset conditions associated with a loss of SOD1 function cannot be ruled out at this stage.…”

Dystonia in veterinary neurology

“…Propofol-induced dystonic movements have been reported anecdotally in dogs (so-called "propofol shakes"). The nature of these shakes T A B L E 2 Additional publications (not included in the consensus report on canine dyskinesia 1 ) related to canine and feline dyskinesia and synopsis of the presented findings [15][16][17][18]71 Publication Synopsis (epileptiform or not) is unknown. A single case report describes propofol-induced dystonia in a Golden Retriever.…”

“…Examples include the reported positive effect of anti-seizure medications and muscle-relaxing drugs such as diazepam on the severity and duration of PxD in dogs. 1,[15][16][17][18] Another example is treatment of spastic paresis in cattle by partial tibial neurectomy. The recent consensus report on dyskinesias in dogs discusses neuroanatomic structures involved in the control of movement and posture, in particular the basal nuclei (e.g., caudate nucleus, putamen) and cerebellum.…”

“…The activity of these neurons, signal transmission, and the activity of the muscles can be modulated or disrupted to ameliorate the clinical signs of disorders featuring dystonia. Examples include the reported positive effect of anti‐seizure medications and muscle‐relaxing drugs such as diazepam on the severity and duration of PxD in dogs 1,15‐18 . Another example is treatment of spastic paresis in cattle by partial tibial neurectomy.…”

Special issue on companion animal genetics: Novel variants discovered in wide variety of diseases in dogs, identification and further characterization of traits in dogs and cats, and the use of microarrays in the detection of aneuploidy in dogs

“…Two point mutations in SOD1 are known to cause degenerative myelopathy in a variety of dog breeds (Zeng et al 2014) and are animal models for amyotrophic lateral sclerosis in humans. In this issue, Mandigers et al (2021) identified a frameshift mutation in the Dutch Markiesje dog breed that leads to an autosomal recessive form of juvenile paroxysmal dyskinesia. This research provides an animal model for a juvenile, progressive spastic tetraplegia, and axial hypotonia (OMIM 618598).…”