Truncating SLC12A6 variants cause different clinical phenotypes in humans and dogs

Clinical, pathological, and genetic findings of a primary hereditary ataxia found in a Malinois dog family are described andcompared with its human counterpart. Based on the family history and the phenotype/genotype relationships alreadydescribed in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exomesequencing identified the SLC12A6 NC_006612.3(XM_014109414.2): c.178_181delinsCATCTCACTCAT (p.(Met60Hisfs*14)) truncating variant. This loss-of-function variant perfectly segregated within the affected Malinois familyin an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, includingMalinois. In humans, SLC12A6 variants cause “agenesis of the corpus callosum with peripheral neuropathy” (ACCPN, aliasAndermann syndrome), owing to a dysfunction of this K+–Cl−cotransporter. However, depending on the variant (includin gtruncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoformdescribed so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis ofthe corpus callosum nor obvious mental retardation have been observ ed in dogs. On the other hand, progressivespinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia -likemuscle contractions have not been descri bed in humans with ACCPN so far. As this is the first report of a naturally occurringdisease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand thecomplex molecular pathophysio logy of SLC12A6-related neurological disorders and to evaluate novel treatment strategies

The novel homozygous KCNJ10 c.986T>C (p.(Leu329Pro)) variant is pathogenic for the SeSAME/EAST homologue in Malinois dogs.

SeSAME/EAST syndrome is a multisystemic disorder in humans, characterised by seizures, sensorineural deafness, ataxia, developmental delay and electrolyte imbalance. It is exclusively caused by homozygous or compound heterozygous variations in the KCNJ10 gene. Here we describe a similar syndrome in two families belonging to the Malinois dog breed, based on clinical, neurological, electrodiagnostic and histopathological examination. Genetic analysis detected a novel pathogenic KCNJ10 c.986T>C (p.(Leu329Pro)) variant that is inherited in an autosomal recessive way. This variant has an allele frequency of 2.9% in the Belgian Malinois population, but is not found in closely related dog breeds or in dog breeds where similar symptoms have been already described. The canine phenotype is remarkably similar to humans, including ataxia and seizures. In addition, in half of the dogs clinical and electrophysiological signs of neuromyotonia were observed. Because there is currently no cure and treatment is nonspecific and unsatisfactory, this canine translational model could be used for further elucidating the genotype/phenotype correlation of this monogenic multisystem disorder and as an excellent intermediate step for drug safety testing and efficacy evaluations before initiating human studies

Chronic vertebral Escherichia coli osteomyelitis in a 4-year-old dog

A 4-year-old, female Malinois shepherd dog was presented for chronic repetitive episodes of severe pain for over a year. Medical imaging findings and a positive blood culture were suggestive of a L2 vertebral bacterial osteomyelitis, most likely of haematogenous origin. The dog responded well to treatment with antibiotics and analgesia. A repeated computed tomography scan 6 months after presentation (and 3 months after antibiotic discontinuation) showed a clear improvement of the vertebral lesions. The dog is still clinically normal and pain-free at the time of writing (3 years after diagnosis)

Paradoxical pseudomyotonia in English Springer and Cocker Spaniels

Background Paramyotonia congenita and Brody disease are well-described conditions in humans, characterized by exercise-induced myotonic-like muscle stiffness. A syndrome similar to Brody disease has been reported in cattle. Reports of a similar syndrome in dogs are scarce. Objectives To define and describe the clinical, diagnostic, and genetic features and disease course of paradoxical pseudomyotonia in Spaniel dogs. Animals Seven client-owned dogs (4 English Springer Spaniels and 3 English Cocker Spaniels) with clinically confirmed episodes of exercise-induced generalized myotonic-like muscle stiffness. Methods Sequential case study. Results All dogs were <24 months of age at onset. The episodes of myotonic-like generalized muscle stiffness always occurred with exercise, and spontaneously resolved with rest in <45 seconds in all but 1 dog. Extreme outside temperatures seemed to considerably worsen episode frequency and severity in most dogs. Complete blood count, serum biochemistry including electrolytes, urinalysis, brain magnetic resonance imaging, cerebrospinal fluid analysis, electromyography, motor nerve conduction velocity, ECG, and echocardiography were unremarkable. Muscle biopsy samples showed moderate but nonspecific muscle atrophy. The episodes seemed to remain stable or decrease in severity and frequency in 6/7 dogs, and often could be decreased or prevented by avoiding the episode triggers. The underlying genetic cause is not identified yet, because no disease-causing variants could be found in the coding sequence or splice sites of the 2 major candidate genes, SCN4A and ATP2A1. Conclusions and Clinical Importance Paradoxical pseudomyotonia is a disease affecting Spaniels. It is of variable severity but benign in most cases

Cytosine arabinoside constant rate infusion without subsequent subcutaneous injections for the treatment of dogs with meningoencephalomyelitis of unknown origin

Background: The administration of cytosine arabinoside (CA) by continuous rate infusion (CRI) at the time of diagnosis has been shown to improve the 3-month survival of dogs diagnosed with meningoencephalomyelitis of unknown origin (MUO), compared to subcutaneous administration. The benefit of administering subsequent sequential CA subcutaneous injections is unknown. This study compares the outcomes of a CA CRI protocol with (CRI+subcutaneous group) or without (CRI group) follow-up CA subcutaneous injections; both groups received adjunctive prednisolone. Methods: Forty-two dogs diagnosed with MUO were recruited (CRI group) and compared with 41 historical control dogs (CRI+subcutaneous group) in a prospective, controlled clinical trial with 36 months of follow-up. Results: Success rates were respectively 64.3 per cent and 65 per cent in the CRI and the CRI+subcutaneous groups at 40 weeks following diagnosis, and 32.5 per cent and 35.9 per cent at 36 months following diagnosis. The median time to relapse was 299 and 285 days for the CRI and the CRI+subcutaneous groups, respectively. No statistically significant difference was found (P=0.05). Conclusion: No clear benefit was identified in the administration of subsequent sequential CA subcutaneous injections after the first administration of CA by CRI for the treatment of dogs diagnosed with MUO

Phenotypic and genetic aspects of hereditary ataxia in dogs

Hereditary ataxias are a large group of neurodegenerative diseases that have cerebellar or spinocerebellar dysfunction as core feature, occurring as an isolated sign or as part of a syndrome. Based on neuropathology, this group of diseases has so far been classified into cerebellar cortical degenerations, spinocerebellar degenerations, cerebellar ataxias without substantial neurodegeneration, canine multiple system degeneration, and episodic ataxia. Several new hereditary ataxia syndromes are described, but most of these diseases have similar clinical signs and unspecific diagnostic findings, wherefore achieving a definitive diagnosis in these dogs is challenging. Eighteen new genetic variants associated with these diseases have been discovered in the last decade, allowing clinicians to reach a definitive diagnosis for most of these conditions, and allowing breeding schemes to adapt to prevent breeding of affected puppies. This review summarizes the current knowledge about hereditary ataxias in dogs, and proposes to add a "multifocal degenerations with predominant (spino)cerebellar component" category regrouping canine multiple system degeneration, new hereditary ataxia syndromes that do not fit in 1 of the previous categories, as well as specific neuroaxonal dystrophies and lysosomal storage diseases that cause major (spino)cerebellar dysfunction

Spinocerebellar ataxia in the Bouvier des Ardennes breed is caused by a KCNJ10 missense variant

Background: In Belgian Malinois, a KCNJ10 variant causes progressive spinocerebellar degeneration. Hypothesis/objectives: Describe the clinical, diagnostic, pathological and genetic features of spinocerebellar degeneration in the Bouvier des Ardennes breed. Animals: Five affected Bouvier des Ardennes puppies with spinocerebellar ataxia (SCA), 8 healthy related dogs, and 63 healthy unrelated Bouvier des Ardennes. Methods: Sequential case study. Results: Clinical signs started at 6 weeks of age in 1 puppy with severe signs of cerebellar disease, and at 7 to 10 weeks of age in the 4 remaining puppies with milder signs of spinocerebellar disease. The first puppy displayed severe intention tremors and rapidly progressive generalized hypermetric ataxia, whereas the 4 others developed a milder progressive SCA. Euthanasia after progression to nonambulatory status was performed by 8 weeks of age in the first puppy, and before 11 months of age in the 4 remaining puppies. Histopathology revealed cerebellar spongy degeneration and a focal symmetrical demyelinating myelopathy. All cases were homozygous for KCNJ10 XM_545752.6:c.986T>C(p.(Leu329Pro)), which is pathogenic for SCA with (or without) myokymia, seizures or both (SAMS) and spongy degeneration and cerebellar ataxia (SDCA) 1 in Belgian Malinois dogs. All sampled parents were heterozygous and none of the healthy dogs were homozygous for this recessive variant. This variant has an allele frequency of 15% in the 63 healthy dogs studied. Conclusions and clinical importance: Inherited spinocerebellar degeneration also affects the Bouvier des Ardennes breed and is caused by a KCNJ10 variant. It can present with a spectrum of severity grades, ranging from severe cerebellar to milder spinocerebellar signs