Canine models of Charcot-Marie-Tooth: MTMR2, MPZ, and SH3TC2 variants in golden retrievers with congenital hypomyelinating polyneuropathy.

Congenital hypomyelinating polyneuropathy (HPN) restricted to the peripheral nervous system was reported in 1989 in two Golden Retriever (GR) littermates. Recently, four additional cases of congenital HPN in young, unrelated GRs were diagnosed via neurological examination, electrodiagnostic evaluation, and peripheral nerve pathology. Whole-genome sequencing was performed on all four GRs, and variants from each dog were compared to variants found across >1,000 other dogs, all presumably unaffected with HPN. Likely causative variants were identified for each HPN-affected GR. Two cases shared a homozygous splice donor site variant in MTMR2, with a stop codon introduced within six codons following the inclusion of the intron. One case had a heterozygous MPZ isoleucine to threonine substitution. The last case had a homozygous SH3TC2 nonsense variant predicted to truncate approximately one-half of the protein. Haplotype analysis using 524 GR established the novelty of the identified variants. Each variant occurs within genes that are associated with the human Charcot-Marie-Tooth (CMT) group of heterogeneous diseases, affecting the peripheral nervous system. Testing a large GR population (n = >200) did not identify any dogs with these variants. Although these variants are rare within the general GR population, breeders should be cautious to avoid propagating these alleles.

Immune-mediated polyneuropathy in cats: Clinical description, electrodiagnostic assessment, and treatment.

BACKGROUND: Suspected immune-mediated polyneuropathy has been increasingly reported in cats, especially in the last decade, but the condition remains poorly understood. OBJECTIVES: Refine the clinical description and review the classification of this condition based on electrodiagnostic investigation and evaluate the benefit of corticosteroid treatment and L-carnitine supplementation. ANIMALS: Fifty-five cats presented with signs of muscular weakness and electrodiagnostic findings consistent with polyneuropathy of unknown origin. METHODS: Retrospective, multicenter study. Data from the medical records were reviewed. The owners were contacted by phone for follow-up at the time of the study. RESULTS: The male-to-female ratio was 2.2. The median age of onset was 10 months, with 91% of affected cats being <3 years of age. Fourteen breeds were represented in the study. The electrodiagnostic findings supported purely motor axonal polyneuropathy. Histological findings from nerve biopsies were consistent with immune-mediated neuropathy in 87% of the tested cats. The overall prognosis for recovery was good to excellent, as all but 1 cat achieved clinical recovery, with 12% having mild sequelae and 28% having multiple episodes during their lifetime. The outcome was similar in cats with no treatment when compared with cats receiving corticosteroids or L-carnitine supplementation. CONCLUSIONS AND CLINICAL IMPORTANCE: Immune-mediated motor axonal polyneuropathy should be considered in young cats with muscle weakness. This condition may be similar to acute motor axonal neuropathy in Guillain-Barré syndrome patients. Based on our results, diagnostic criteria have been proposed.

Serum anti-GM2 and anti-GalNAc-GD1a ganglioside IgG antibodies are biomarkers for immune-mediated polyneuropathies in cats.

Recent work identified anti-GM2 and anti-GalNAc-GD1a IgG ganglioside antibodies as biomarkers in dogs clinically diagnosed with acute canine polyradiculoneuritis, in turn considered a canine equivalent of Guillain-Barré syndrome. This study aims to investigate the serum prevalence of similar antibodies in cats clinically diagnosed with immune-mediated polyneuropathies. The sera from 41 cats clinically diagnosed with immune-mediated polyneuropathies (IPN), 9 cats with other neurological or neuromuscular disorders (ONM) and 46 neurologically normal cats (CTRL) were examined for the presence of IgG antibodies against glycolipids GM1, GM2, GD1a, GD1b, GalNAc-GD1a, GA1, SGPG, LM1, galactocerebroside and sulphatide. A total of 29/41 IPN-cats had either anti-GM2 or anti-GalNAc-GD1a IgG antibodies, with 24/29 cats having both. Direct comparison of anti-GM2 (sensitivity: 70.7%; specificity: 78.2%) and anti-GalNAc-GD1a (sensitivity: 70.7%; specificity: 70.9%) antibodies narrowly showed anti-GM2 IgG antibodies to be the better marker for identifying IPN-cats when compared to the combined ONM and CTRL groups (P = .049). Anti-GA1 and/or anti-sulphatide IgG antibodies were ubiquitously present across all sample groups, whereas antibodies against GM1, GD1a, GD1b, SGPG, LM1 and galactocerebroside were overall only rarely observed. Anti-GM2 and anti-GalNAc-GD1a IgG antibodies may serve as serum biomarkers for immune-mediated polyneuropathies in cats, as previously observed in dogs and humans.

Tongue atrophy as a neurological finding in hereditary polyneuropathy in Alaskan malamutes.

BACKGROUND: Tongue atrophy with wrinkling as a clinical sign of inherited polyneuropathies has not been reported in dogs. OBJECTIVES: Clinically describe tongue atrophy as well as morphology of the tongue and hypoglossal nerve in Alaskan malamute polyneuropathy (AMPN). ANIMALS: Six client-owned Alaskan malamute dogs diagnosed with AMPN, all homozygous for the causative mutation in the N-myc downstream-regulated gene 1 (NDRG1) and 1 neurologically normal control Alaskan malamute. METHODS: Prospective case study. Clinical and neurological examinations were performed on affected dogs. Necropsy samples from the tongue muscle and hypoglossal nerve were examined by light and electron microscopy. RESULTS: All affected dogs had abnormal wrinkles and grooves on the dorsal surface of the tongue, a clinical sign not described previously in dogs with AMPN. Electromyography of the tongue performed in 2 dogs showed spontaneous activity. Five affected dogs underwent necropsy studies. Histopathology of the tongue showed groups of angular atrophic myofibers and changes in the hypoglossal nerve included thinly myelinated fibers, small onion bulbs, folded myelin, and axonal degeneration. CONCLUSION AND CLINICAL IMPORTANCE: Histopathologic changes in the tongue and hypoglossal nerve were consistent with previously reported changes in skeletal muscle and other nerves from dogs with AMPN. Therefore, we conclude that macroscopic tongue atrophy is part of the disease phenotype of AMPN and should be considered a potential clinical sign in dogs with polyneuropathies.

EARLY-ONSET LEUKOENCEPHALOMYELOPATHY AND POLYNEUROPATHY IN EASTERN QUOLLS (DASYURUS VIVERRINUS) IN THE EUROPEAN CAPTIVE POPULATION.

Leukoencephalomyelopathy (LEM) is suggested to be an age-related degenerative condition in geriatric Eastern quolls (Dasyurus viverrinus), manifesting in animals greater than 3.5 yr of age. This case series describes four LEM cases from two zoologic collections; three in nongeriatric animals, with one only 1 yr of age, and details advanced diagnostic investigation, including magnetic resonance imaging, cerebrospinal fluid analysis, and electrodiagnostic studies, not previously reported in Eastern quolls. Animals presented clinically with forelimb proprioceptive deficits and hindlimb and lumbar muscle hypotrophy, which were not noted in previous reports, in addition to hindlimb ataxia. Blindness and emaciation, which have been reported previously, were not seen. Disease progression was variable, and time from first clinical signs to euthanasia ranged from 46 days to over 2 yr. Histopathologic findings in the central nervous system were typical of those in previous LEM cases; concomitant polyneuropathy was observed in two quolls. Our findings suggest that age-related degeneration may not be the only cause of LEM in Eastern quolls. Because all quolls were related, a familial component cannot be excluded. LEM should be further investigated for its potential impact on future captive breeding programs, and our findings suggest that daily quality-of-life assessment should guide euthanasia of affected animals.

Postpartum Polyneuropathy in a Mare: A Case Report.

Obstetric paralysis is a generic term used to describe postpartum locomotor alterations resulting from nerve damage, widely reported in cattle, but rare in equines. The aim of this study is to report a case of a peripheral polyneuropathy in a primiparous mare, 3 years old, of Mangalarga Marchador breed, after a dystocia lasting approximately 12 hours. At the time of delivery, the head of the fetus was exposed in the vulva and there was flexion of the thoracic limbs. These events culminated in a framework of extreme abduction of the pelvic limbs, thus generating functional impotence and leading the animal to adopt a frog anddecubitus position. After three days of treatment with no improvement in the clinical framework, the animal was euthanized. In the postmortem examination, perineural hemorrhagic lesions were observed in the obturator and sciatic nerves, characterizing the diagnosis of obstetric paralysis. It is possible the outcome of the case would have been satisfactory if there had been an early fetotomy or postpartum treatment had been more prolonged; however, these measures depend on the availability of equipment, conditions of care, and consideration of the owner.

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy.

Laryngeal paralysis associated with a generalized polyneuropathy (LPPN) most commonly exists in geriatric dogs from a variety of large and giant breeds. The purpose of this study was to discover the underlying genetic and molecular mechanisms in a younger-onset form of this neurodegenerative disease seen in two closely related giant dog breeds, the Leonberger and Saint Bernard. Neuropathology of an affected dog from each breed showed variable nerve fiber loss and scattered inappropriately thin myelinated fibers. Using across-breed genome-wide association, haplotype analysis, and whole-genome sequencing, we identified a missense variant in the CNTNAP1 gene (c.2810G>A; p.Gly937Glu) in which homozygotes in both studied breeds are affected. CNTNAP1 encodes a contactin-associated protein important for organization of myelinated axons. The herein described likely pathogenic CNTNAP1 variant occurs in unrelated breeds at variable frequencies. Individual homozygous mutant LPPN-affected Labrador retrievers that were on average four years younger than dogs affected by geriatric onset laryngeal paralysis polyneuropathy could be explained by this variant. Pathologic changes in a Labrador retriever nerve biopsy from a homozygous mutant dog were similar to those of the Leonberger and Saint Bernard. The impact of this variant on health in English bulldogs and Irish terriers, two breeds with higher CNTNAP1 variant allele frequencies, remains unclear. Pathogenic variants in CNTNAP1 have previously been reported in human patients with lethal congenital contracture syndrome and hypomyelinating neuropathy, including vocal cord palsy and severe respiratory distress. This is the first report of contactin-associated LPPN in dogs characterized by a deleterious variant that most likely predates modern breed establishment.

Juvenile-onset motor polyneuropathy in Siberian cats.

BACKGROUND: Polyneuropathies are infrequently described in cats. There is a genetic predisposition in several breeds. OBJECTIVE: To clinically characterize a novel motor polyneuropathy in a family of Siberian cats. ANIMALS: Thirteen closely related Siberian cats, 4 clinically affected and 9 clinically unaffected individuals. METHODS: Retrospective study. Clinical data and pedigree information were obtained from the medical records and breeder. Electrodiagnostic testing and muscle and peripheral nerve biopsy samples were obtained from 1 affected cat. Follow-up information was obtained for all affected cats. RESULTS: Onset of signs was 4 to 10 months in affected cats. Clinical signs were progressive or waxing/waning neuromuscular weakness (4/4), normal sensory function (4/4), and variably decreased withdrawal reflexes (3/4). All cats returned to normal neurologic function within 1 to 4 weeks. All cats had a recurrence of weakness (3/4 had 1 recurrent episode, 1/4 had 3 relapses) from which they recovered fully. In 1 cat, electromyography and motor nerve conduction studies showed multicentric spontaneous activity, normal motor nerve conduction velocity, reduced compound muscle action potential amplitude, and polyphasia. Histologic evaluation of muscle and nerve in that cat showed mild muscle atrophy consistent with recent denervation, endoneurial and perineurial edema, and mild mononuclear cell infiltration within intramuscular nerve branches and a peripheral nerve. Pedigree analysis suggests an autosomal recessive mode of inheritance, although neither a genetically complex/polygenic condition nor an acquired inflammatory polyneuropathy can be ruled-out. CONCLUSIONS AND CLINICAL IMPORTANCE: We describe a motor polyneuropathy in juvenile Siberian cats characterized by self-limiting weakness with potential relapse.

Long-term outcome of Miniature Schnauzers with genetically confirmed demyelinating polyneuropathy: 12 cases.

BACKGROUND: A demyelinating polyneuropathy with focally folded myelin sheaths was reported in 3 Miniature Schnauzers in France in 2008 and was predicted to represent a naturally occurring canine homologue of Charcot-Marie-Tooth (CMT) disease. A genetic variant of MTRM13/SBF2 has been identified as causative in affected Miniature Schnauzers with this polyneuropathy. OBJECTIVE: To provide data on the long-term progression in affected Miniature Schnauzers from Spain confirmed with the MTRM13/SBF2 genetic variant. ANIMALS: Twelve Miniature Schnauzers presented between March 2013 and June 2019. METHODS: Only dogs presented with consistent clinical signs and homozygous for the MTRM13/SBF2 genetic variant were included. Clinical signs, age of onset and presentation, time from onset to presentation, treatment, outcome, and time from diagnosis to final follow-up were retrospectively reviewed. RESULTS: The hallmark clinical signs at the time of presentation were regurgitation with radiologically confirmed megaesophagus (11/12) and aphonic bark (11/12) with or without obvious neuromuscular weakness despite electrodiagnostic evidence of appendicular demyelinating polyneuropathy. Age of onset and clinical presentation were 3-18 and 4-96 months, respectively. Treatment was mostly symptomatic and consisted of head elevation during meals, antacids, prokinetics, bethanechol, sildenafil, mirtazapine, or some combination of these. During the follow-up period (7-73 months), clinical signs were unchanged in (11/12) cases with aspiration pneumonia developing occasionally (6/12) and being the cause of death in 1 dog. CONCLUSIONS AND CLINICAL IMPORTANCE: Demyelinating polyneuropathy of Miniature Schnauzers tends to remain stable over the long term leading to a good prognosis with preventive feeding measures and symptomatic treatment to control aspiration pneumonia.

Polyneuropathy in Young Siberian Huskies Caused by Degenerative and Inflammatory Diseases.

Polyneuropathy is defined as the simultaneous dysfunction of several peripheral nerves. In dogs, a number of breeds are predisposed to a variety of immune-mediated and/or degenerative inherited forms of polyneuropathy, with laryngeal paralysis and/or megaesophagus as important clinical features of many of these conditions. This case series describes degenerative and inflammatory polyneuropathies in 7 young Siberian huskies that were categorized based on clinicopathological characteristics as follows: (1) slowly progressive laryngeal paralysis and megaesophagus caused by primary axonal degeneration with large fiber loss (n = 2); (2) slowly progressive polyneuropathy without megaesophagus or laryngeal paralysis caused by primary axonal degeneration with large fiber loss (n = 2); (3) acute inflammatory demyelinating neuropathy causing sensory, motor and autonomic nerve deficits (n = 2); and (4) ganglioradiculitis (sensory neuronopathy; n = 1). Based on the predominantly young age at onset, slow progression, relatedness of affected dogs, and clinical and pathological similarities with inherited neuropathies reported in other dog breeds, a hereditary basis for the degenerative polyneuropathies in Siberian huskies is suspected. However, 5 different mutations in 3 genes known to cause polyneuropathy in other dog breeds (NDRG1, ARHGEF10, or RAB3GAP1) were not detected in the affected Siberian huskies suggesting that more genetic variants remain to be identified. This study highlights the varied underlying lesions of polyneuropathies in young Siberian huskies.

Cell and context-dependent sorting of neuropathy-associated protein NDRG1 - insights from canine tissues and primary Schwann cell cultures.

BACKGROUND: Mutations in the N-myc downstream-regulated gene 1 (NDRG1) can cause degenerative polyneuropathy in humans, dogs, and rodents. In humans, this motor and sensory neuropathy is known as Charcot-Marie-Tooth disease type 4D, and it is assumed that analogous canine diseases can be used as models for this disease. NDRG1 is also regarded as a metastasis-suppressor in several malignancies. The tissue distribution of NDRG1 has been described in humans and rodents, but this has not been studied in the dog. RESULTS: By immunolabeling and Western blotting, we present a detailed mapping of NDRG1 in dog tissues and primary canine Schwann cell cultures, with particular emphasis on peripheral nerves. High levels of phosphorylated NDRG1 appear in distinct subcellular localizations of the Schwann cells, suggesting signaling-driven rerouting of the protein. In a nerve from an Alaskan malamute homozygous for the disease-causing Gly98Val mutation in NDRG1, this signal was absent. Furthermore, NDRG1 is present in canine epithelial cells, predominantly in the cytosolic compartment, often with basolateral localization. Constitutive expression also occurs in mesenchymal cells, including developing spermatids that are transiently positive for NDRG1. In some cells, NDRG1 localize to centrosomes. CONCLUSIONS: Overall, canine NDRG1 shows a cell and context-dependent localization. Our data from peripheral nerves and primary Schwann cell cultures suggest that the subcellular localization of NDRG1 in Schwann cells is dynamically influenced by signaling events leading to reversible phosphorylation of the protein. We propose that disease-causing mutations in NDRG1 can disrupt signaling in myelinating Schwann cells, causing disturbance in myelin homeostasis and axonal-glial cross talk, thereby precipitating polyneuropathy.

Juvenile-onset polyneuropathy in American Staffordshire Terriers.

BACKGROUND: The only hereditary neurologic disorder described so far in American Staffordshire Terriers is adult-onset cerebellar degeneration secondary to ceroid lipofuscinosis. We have seen several dogs with a newly recognized neurological disease characterized by locomotor weakness with or without respiratory signs and juvenile onset consistent with degenerative polyneuropathy of genetic origin. OBJECTIVES: To characterize a novel polyneuropathy in juvenile American Staffordshire Terriers. ANIMALS: Fourteen American Staffordshire Terriers presented with clinical signs consistent with juvenile-onset polyneuropathy at 5 veterinary hospitals between May 2005 and July 2017. METHODS: Case series. Dogs were included retrospectively after a diagnosis of degenerative polyneuropathy had been confirmed by nerve biopsy. Clinical, pathological, electrophysiological, histological data, and outcome were reviewed and a pedigree analysis performed. RESULTS: All dogs displayed clinical signs of neuromuscular disease with generalized motor and sensory involvement, associated with focal signs of laryngeal paralysis (10/14 dogs) and megaesophagus (1/14 dogs). Histopathological findings were consistent with degenerative polyneuropathy. Follow-up was available for 11 dogs, and 3 dogs were euthanized shortly after diagnosis. In these 11 dogs, the disease was slowly progressive and the animals maintained good quality of life with ability to walk. Pedigree analysis was mostly consistent with an autosomal recessive mode of inheritance. CONCLUSIONS AND CLINICAL IMPORTANCE: Juvenile polyneuropathy, associated with laryngeal paralysis, is a newly described entity in American Staffordshire Terriers, and results from degenerative neuropathy. When surgery for laryngeal paralysis is performed, lifespan may be similar to that of normal dogs even though affected dogs have locomotor disturbance.

Acute polyneuromyopathy with respiratory failure secondary to monensin intoxication in a dog.

OBJECTIVE: To describe a successfully managed case of polyneuropathy and respiratory failure secondary to presumed monensin intoxication. CASE SUMMARY: A 9-month-old Australian Shepherd was evaluated for progressive generalized weakness and respiratory distress. Several days preceding presentation, the dog was seen playing with a monensin capsule, and had free access to a barn where the product was stored and where chewed capsules were subsequently found. The dog was presented with flaccid tetraparesis, hyperthermia, and severe respiratory distress. Bloodwork and urinalysis revealed marked increase in serum creatine kinase concentration and presumed myoglobinuria. Cardiac troponin I level was markedly increased. Management included mechanical ventilation for 5 days, fluid-therapy, active cooling, antimicrobial therapy, analgesia, gastroprotectants, antiemetics, enteral feedings, continuous nursing care, and physiotherapy. Intravenous lipid rescue therapy was administered with lack of improvement in respiratory function and muscle strength. The patient completely recovered and was discharged after 12 days of hospitalization. NEW OR UNIQUE INFORMATION PROVIDED: Monensin intoxication should be considered in the differential diagnosis of acute polyneuromyopathy and respiratory failure in dogs with access to this compound. Respiratory failure secondary to monensin intoxication does not necessarily carry a poor prognosis if mechanical ventilation can be provided as a bridge until return of respiratory function is achieved.

Acquired equine polyneuropathy of Nordic horses: A conspicuous inclusion body schwannopathy.

Acquired equine polyneuropathy (AEP), formerly also known as Scandinavian knuckling syndrome, is one of the most prevalent polyneuropathies in equids in Norway and Sweden, with more than 400 cases registered since first observations in 1995. Despite geographical clustering and an association to forage feeding, its aetiology remains unknown. Clinically AEP is characterized by knuckling due to dysfunction of metatarsophalangeal extensor muscles. This neuropathological study aimed to gain further insights in the pathobiology of AEP and its underlying aetiopathogenesis. We thereby confirmed that all affected horses suffered from similar large fibre neuropathy, exhibiting conspicuous Schwann cell inclusions in most samples, suggestive of a primary disruption of Schwann cell metabolism leading to inclusion body schwannopathy with secondary inflammatory changes. The degree of nerve pathology was not predictive of clinical outcome.

Re-emergence of hereditary polyneuropathy in Scandinavian Alaskan malamute dogs-old enemy or new entity? A case series.

A homozygous mutation has been identified in the N-myc downstream-regulated gene 1 (NDRG1) in recent cases of polyneuropathy in Alaskan malamute dogs from the Nordic countries and USA. The objective of the present study was to determine if cases diagnosed 30-40 years ago with polyneuropathy in the Alaskan malamute breed in Norway had the same hereditary disease as the recent cases. Fourteen historical cases and 12 recently diagnosed Alaskan malamute dogs with hereditary polyneuropathy, and their parents and littermates (n = 88) were included in this study (total n = 114). After phenotyping of historical and recent cases, NDRG1 genotyping was performed using DNA extracted from archived material from five Norwegian dogs affected by the disease in the late 1970s and 1980s. In addition, pedigrees were analysed. Our study concluded that historical and recent phenotypic polyneuropathy cases were carrying the same NDRG1-mutation. The pedigree analysis showed that all affected Alaskan malamute cases with polyneuropathy could be traced back to one common ancestor of North American origin. By this study, a well-documented example of the silent transmission of recessive disease-causing alleles through many generations is provided, demonstrated by the re-emergence of a phenotypically and genetically uniform entity in the Scandinavian Alaskan malamute population.

Bovine and murine models highlight novel roles for SLC25A46 in mitochondrial dynamics and metabolism, with implications for human and animal health.

Neuropathies are neurodegenerative diseases affecting humans and other mammals. Many genetic causes have been identified so far, including mutations of genes encoding proteins involved in mitochondrial dynamics. Recently, the "Turning calves syndrome", a novel sensorimotor polyneuropathy was described in the French Rouge-des-Prés cattle breed. In the present study, we determined that this hereditary disease resulted from a single nucleotide substitution in SLC25A46, a gene encoding a protein of the mitochondrial carrier family. This mutation caused an apparent damaging amino-acid substitution. To better understand the function of this protein, we knocked out the Slc25a46 gene in a mouse model. This alteration affected not only the nervous system but also altered general metabolism, resulting in premature mortality. Based on optic microscopy examination, electron microscopy and on biochemical, metabolic and proteomic analyses, we showed that the Slc25a46 disruption caused a fusion/fission imbalance and an abnormal mitochondrial architecture that disturbed mitochondrial metabolism. These data extended the range of phenotypes associated with Slc25a46 dysfunction. Moreover, this Slc25a46 knock-out mouse model should be useful to further elucidate the role of SLC25A46 in mitochondrial dynamics.

Long-term follow-up of Norwegian horses affected with acquired equine polyneuropathy.

BACKGROUND: Acquired equine polyneuropathy (AEP), a neurological disease clinically characterised by knuckling of metatarsophalangeal joints, has been described in numerous Nordic horses during the last 20 years. Although clinical recovery has been reported, large-scale data on long-term follow-up of survivors have been lacking. OBJECTIVES: To describe long-term survival of AEP affected horses registered in Norway, with a focus on athletic performance and possible residual clinical signs connected to the disease. STUDY DESIGN: A retrospective cohort study. METHODS: The study includes 143 horses recorded with AEP in Norway from 2000 to 2012, with the follow-up period continuing until 2015. Participating owners of survivors completed a standardised questionnaire, providing information on disease and convalescence, management, performance-level and possible residual clinical signs. To investigate the follow-up of survivors, we performed 2 multivariable linear regression models. RESULTS: The follow-up time of survivors was 1.0-14.5 years (median 5.3, interquartile range 2.5-7.2). Fifty-seven horses survived and all but 3 horses returned to previous or higher level of performance. However, possible disease-related residual clinical signs were reported in 14/57 horses. Forty-nine of the survivors were in athletic use at time of contact. The majority of survivors were categorised with low severity-grades at time of diagnosis and the initial grade was significantly associated with time to resumed training. Only 3 horses had experienced relapse/new attack during the follow-up period. MAIN LIMITATION: Athletic performance was judged by owners, which renders a possible source of bias. CONCLUSIONS: Although AEP is a potential fatal disease, most survivors will recover and return to minimum previous level of athletic performance. Some horses display residual clinical signs, but often without negative effect on performance and relapse of disease is rare.

Designing a field trial of an equine grass sickness vaccine: A questionnaire-based feasibility study.

Without an experimental model of equine grass sickness (EGS), a randomised controlled field trial (RCT) represents the only method of evaluating the efficacy of Clostridium botulinum type C vaccination in preventing naturally occurring disease. Clinical trial feasibility is an important aspect of preliminary work undertaken prior to initiating RCTs, estimating parameters that are important for study design. This cross-sectional study aimed to assess the feasibility of conducting a nationwide RCT of a candidate vaccine for EGS based on responses from a sample of British equine veterinary practices (n = 119/284). Seventy-three percent of practices had attended ≥1 EGS case within the preceding 2 years (median four cases), and 51.3% regularly attended recurrently affected premises. Veterinary surgeons had greater confidence diagnosing acute/subacute EGS based solely on history and clinical signs compared to chronic EGS. Ninety-one percent of respondents (n = 103/113) considered the proposed RCT to be important/very important to equine veterinary research. Ninety-one percent of respondents (n = 102/112) indicated preparedness to assist in owner recruitment and 92.9% (n = 104/112) indicated willingness to participate in a RCT. The most frequent reasons for practices declining to participate were low incidence of EGS (n = 4), did not believe clients would wish to participate (n = 3) and amount of paperwork/data collection involved (n = 2). There was considerable support amongst participating veterinary practices for a RCT evaluating the efficacy of Clostridium botulinum vaccination for the prevention of EGS in Britain. Substantial proportions of participating practices would be prepared to participate in the RCT and regularly attended EGS-affected premises that would meet trial inclusion criteria.

Electrodiagnostic studies in presumptive primary hypothyroidism and polyneuropathy in dogs with reevaluation during hormone replacement therapy.

BACKGROUND: Peripheral neuropathy is the most common neurological manifestation of canine hypothyroidism. Data concerning electrodiagnostic studies in hypothyroid associated polyneuropathy in dogs are very limited and usually lack a reevaluation after hormone replacement therapy. The objective of this study was to perform a detailed, retrospective analysis of electromyographic (EMG), motor nerve conduction velocity (MNCV), F-wave and brainstem auditory evoked response (BAER) findings in 24 dogs with presumptive primary hypothyroidism and polyneuropathy with a comparison of the results before and after initiation of levothyroxine treatment with the assessment of the clinical outcome. RESULTS: The results obtained from hypothyroid dogs showed a significant reduction in MNCV at a proximal-distal and middle-distal stimulation, decreased amplitudes of compound muscle action potentials (CMAP), an increased CMAP duration and a prolonged distal latency prior to treatment. Fifty percent of the dogs had an increased F-wave latency. A normal BAER recording was found in 78 % of the hypothyroid patients without vestibular impairment. Bilaterally increased peak V latencies and increased interpeak I-V latencies were found in the remaining individuals. Dogs with concurrent vestibular impairment had ipsilaterally increased peak latencies with normal interpeak latencies and decreased amplitudes of wave I and II. A comparison of the findings before and after 2 months of treatment revealed a decrease in the pathological activity on EMG, an improvement of proximal, middle and distal CMAP amplitudes and an increase in the proximal-distal conduction velocity in all dogs. F-wave latency improved in 38 % of dogs. The BAER reexamination revealed a persistent prolongation of peak I, II, III and V latencies and decreased wave I amplitude on the affected side in all dogs manifesting vestibular signs. Conversely, in dogs without vestibular signs, the peak V and interpeak I-V latencies decreased to normal values after a given time of the treatment. CONCLUSIONS: The results indicate a demyelinating and axonal pattern of polyneuropathy in dogs with suspected hypothyroidism. Most of the patients without vestibular signs showed neither peripheral nor central auditory pathway impairment, concurrent to the generalized neuropathy. The follow-up examination showed a very good clinical outcome and only partial improvement in electrophysiological assessment.

A Homozygous RAB3GAP1:c.743delC Mutation in Rottweilers with Neuronal Vacuolation and Spinocerebellar Degeneration.

BACKGROUND: A variety of presumed hereditary, neurologic diseases have been reported in young Rottweilers. Overlapping ages of onset and clinical signs have made antemortem diagnosis difficult. One of these diseases, neuronal vacuolation and spinocerebellar degeneration (NVSD) shares clinical and histological features with polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV), a recently described hereditary disease in Black Russian Terriers (BRTs). Dogs with POANV harbor mutations in RAB3GAP1 which codes for a protein involved in membrane trafficking. HYPOTHESIS: Rottweilers with NVSD will be homozygous for the RAB3GAP1:c.743delC allele associated with POANV in BRTs. ANIMALS: Eight Rottweilers with NVSD confirmed at necropsy, 128 Rottweilers without early onset neurologic signs, and 468 randomly selected dogs from 169 other breeds. METHODS: Retrospective case-control study. Dogs were genotyped for the RAB3GAP1:c.743delC allele with an allelic discrimination assay. RESULTS: All 8 NVSD-affected dogs were homozygous for the RAB3GAP1:c.743delC allele while the 128 NVSD-free Rottweilers were either homozygous for the reference allele (n = 105) or heterozygous (n = 23) and the 468 genotyped dogs from other breeds were all homozygous for the reference allele. CONCLUSIONS AND CLINICAL IMPORTANCE: The RAB3GAP1:c.743delC mutation is associated with a similar phenotype in Rottweilers and BRTs. Identification of the mutation permits a DNA test that can aid in the diagnosis of NVSD and identify carriers of the trait so that breeders can avoid producing affected dogs. Disruption of membrane trafficking could explain the neuronal vacuolation seen in NVSD and other spongiform encephalopathies.