The c.126C>A(p.(Cys42Ter)) SLC7A10 nonsense variant is a candidate causative variant for paradoxical pseudomyotonia in English Cocker and Springer Spaniels.

Paradoxical pseudomyotonia has previously been described in the English Cocker Spaniel (ECS) and English Springer Spaniel (ESS) breeds, without the identification of potentially causative variants. This disease is characterised by episodes of exercise-induced generalised myotonic-like muscle stiffness, phenotypically similar to congenital pseudomyotonia in cattle, and paramyotonia congenita and Brody disease in people. Four additional affected ESS dogs with paradoxical pseudomyotonia are described in this report, together with the identification of the autosomal recessive c.126C>A(p.(Cys42Ter)) SLC7A10 nonsense variant as candidate disease-causing variant in both ECS and ESS. The variant has an estimated prevalence of 2.5% in both breeds in the British study samples, but was not identified in the Belgian study samples. Genetic testing-based breeding should be a useful tool to eliminate this disease in the future, although an effective treatment option is available for severely affected dogs.

Incidence and clinical characterisation of thoracolumbar intervertebral disc extrusions in Basset Hounds compared with Dachshunds.

BACKGROUND: The Basset Hound is the largest chondrodystrophic breed predisposed to thoracolumbar intervertebral disc extrusion (TL-IVDE). However, literature describing this particular breed in terms of incidence, signalment, anatomical location, clinical severity and short-term outcome of TL-IVDE is lacking. METHODS: The medical histories of Dachshunds and Basset Hounds presenting to three neurology departments were retrospectively assessed. Information collected for each dog included signalment, whether it had received a diagnosis of TL-IVDE, duration of clinical signs, affected discs and anatomical region and neurological grading at presentation and discharge. RESULTS: A total of 270 Dachshunds and 188 Basset Hounds were included for incidence analysis. Of these, 154 Dachshunds and 68 Basset Hounds with confirmed TL-IVDE were included for signalment, anatomical location, clinical severity and short-term outcome analysis. Statistical analysis indicated a significantly higher incidence of TL-IVDE in Dachshunds than in Basset Hounds (77.4% vs. 36.2%, p < 0.05). Basset Hounds presenting to a neurology department were older (median 87.5 months vs. 66.5 months), had a greater proportion of midlumbar IVDE (L2-L5) and were more frequently ambulatory at discharge than Dachshunds. Only one Basset Hound presented as paraplegic without nociception, compared with 16 Dachshunds (1.5% vs. 10.4%). LIMITATIONS: The study had a retrospective design and included multicentric non-standardised cases. CONCLUSION: TL-IVDE incidence was higher in Dachshunds than in Basset Hounds. Basset Hounds were older at presentation, frequently affected more caudally in the vertebral column and more frequently ambulatory at discharge than Dachshunds. The differences found in this study could aid in the development of preventive strategies.

Case report: Immune remission from generalized myasthenia gravis in a dog with a thymoma and cholangiocellular carcinoma.

A 9-year-old male neutered Cockapoo was presented with an acute and progressive history of exercise induced weakness involving all limbs, and bilateral decreased ability to blink. Investigations revealed generalized myasthenia gravis alongside the presence of a thymoma and a cholangiocellular carcinoma. Symptomatic treatment through pyridostigmine bromide was used to control clinical signs, and complete surgical removal of the thymoma and cholangiocellular carcinoma was performed. Serum acetylcholine receptor antibody concentration was measured serially. Clinical remission defined as resolution of clinical signs alongside discontinuation of treatment was achieved by day 251 (8.2 months). Immune remission defined as normalization of serum acetylcholine receptor antibody concentration alongside resolution of clinical signs and discontinuation of treatment was achieved by day 566 (18.5 months). Neurological examination was normal, and the owners did not report any clinical deterioration during the final follow-up appointment on day 752 (24 months), hence outcome was considered excellent. This is the first report describing the temporal evolution of serum acetylcholine receptor antibody concentration in a dog with thymoma-associated myasthenia gravis which achieved immune remission following thymectomy. Treatment was successfully discontinued without any evidence of clinical deterioration thereafter despite serum acetylcholine receptor antibody concentration not normalizing for another 315 days (10 months).

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.

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.

Generalized myokymia, or neuromyotonia, or both in dogs with or without spinocerebellar ataxia.

BACKGROUND: KCNJ10 and CAPN1 variants cause "spinocerebellar" ataxia in dogs, but their association with generalized myokymia and neuromyotonia remains unclear. OBJECTIVE: To investigate the association between KCNJ10 and CAPN1 and myokymia or neuromyotonia, with or without concurrent spinocerebellar ataxia. ANIMALS: Thirty-three client-owned dogs with spinocerebellar ataxia, myokymia neuromytonia, or a combination of these signs. METHODS: Genetic analysis of a cohort of dogs clinically diagnosed with spinocerebellar ataxia, myokymia or neuromyotonia. KCNJ10 c.627C>G and CAPN1 c.344G>A variants and the coding sequence of KCNA1, KCNA2, KCNA6, KCNJ10 and HINT1 were sequenced using DNA extracted from blood samples. RESULTS: Twenty-four Jack Russell terriers, 1 Jack Russell terrier cross, 1 Dachshund and 1 mixed breed with spinocerebellar ataxia were biallelic (homozygous) for the KCNJ10 c.627C>G variant. Twenty-one of those dogs had myokymia, neuromyotonia, or both. One Parson Russell terrier with spinocerebellar ataxia alone was biallelic for the CAPN1 c.344G>A variant. Neither variant was found in 1 Jack Russell terrier with ataxia alone, nor in 3 Jack Russell terriers and 1 Yorkshire terrier with myokymia and neuromyotonia alone. No other causal variants were found in the coding sequence of the investigated candidate genes in these latter 5 dogs. CONCLUSION: The KCNJ10 c.627C>G variant, or rarely the CAPN1 c.344G>A variant, was confirmed to be the causal variant of spinocerebellar ataxia. We also report the presence of the KCNJ10 c.627C>G variant in the Dachshund breed. In dogs with myokymia and neuromyotonia alone the reported gene variants were not found. Other genetic or immune-mediated causes should be investigated to explain the clinical signs of these cases.

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.

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 and compared with its human counterpart. Based on the family history and the phenotype/genotype relationships already described in humans and dogs, a causal variant was expected to be found in KCNJ10. Rather surprisingly, whole-exome sequencing 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 family in an autosomal recessive way and was not found in 562 additional reference dogs from 18 different breeds, including Malinois. In humans, SLC12A6 variants cause "agenesis of the corpus callosum with peripheral neuropathy" (ACCPN, alias Andermann syndrome), owing to a dysfunction of this K+-Cl- cotransporter. However, depending on the variant (including truncating variants), different clinical features are observed within ACCPN. The variant in dogs encodes the shortest isoform described so far and its resultant phenotype is quite different from humans, as no signs of peripheral neuropathy, agenesis of the corpus callosum nor obvious mental retardation have been observed in dogs. On the other hand, progressive spinocerebellar ataxia, which is the most important feature of the canine phenotype, hindlimb paresis, and myokymia-like muscle contractions have not been described in humans with ACCPN so far. As this is the first report of a naturally occurring disease-causing SLC12A6 variant in a non-human species, the canine model will be highly valuable to better understand the complex molecular pathophysiology 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.