Fitzpatrick Referrals Orthopedics and Neurology, Halfway Lane, Eashing, Godalming, Surrey, United Kingdom, Roles Formal analysis, Complete blood count, serum biochemistry, urinalysis and cerebrospinal fluid are normal [8, 9]. Yes Key G. Progression Survey 2013 [cited 2016 16th April]. A survey was submitted to owners of MWHD which were homozygous for Epm2b mutation (breed club testing program) or had late onset reflex myoclonus and clinical diagnosis of LD. Signalment and age of onset of first clinical signs in a cohort of data for 27 MWHD with confirmed and suspected LD. Ahonen S, Grossman TP, Wang P, Turnbull J, Zhao X, Minassian BA. Before The mean age of onset of clinical signs was 6.94 years which correlated with the median age of onset of 7 years. As such, work is actively underway to identify glycogen synthase inhibitors towards a potential therapy for LD, human and canine. This mutation consists of a massive expansion of a dodecamer repeat sequence present exclusively in the canine (and generally canid) Epm2b gene, leading to near-absent expression and loss of function of the gene [1, 12]. Despite early promising results [42] longer term observations suggest that feeding a low CRcarbohydrate and/or high antioxidant diet does not delay onset of disease in LD dogs. Pederson BA, Turnbull J, Epp JR, Weaver SA, Zhao X, Pencea N, et al. Writing review & editing, Current address: BluePearl Veterinary Partners Michigan, Southfield, Michigan, United States of America, Affiliation Federal government websites often end in .gov or .mil. The Dachshund Breed Council is affiliated with the UK Kennel Club and represents the interests of sixteen UK Dachshund Breed Clubs and appoints Health and Welfare Sub-committees to develop policies and coordinate plans for Dachshund breed health improvement. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript with the exception of the Dachshund Breed Council which has a Health and Welfare subcommittee which instigated the data collection but did not play a role in analysis. PLoS ONE 12(8): https://doi.org/10.1371/journal.pone.0182024, Editor: Francesc Palau, Sant Joan de Du Children's Hospital, SPAIN, Received: December 15, 2016; Accepted: July 11, 2017; Published: August 2, 2017. B. Electron micrograph of a LB in the terminal cytoplasm of a dendrite. The authors are grateful to the Dachshund Breed Council, the Wire Haired Dachshund club and Lafora Subcommittee for enabling this project. LD, in this sense, can be regarded as a canine genome particular disease, and is likely to continue to be seen in different purebred breeds with each recurrence of the expansion mutation. Owners of affected dogs stated that they were unable to walk the dog off the leash because if it occurred then the affected dog could run off uncharacteristically. Both are mutation positive for LD. In the untested group the most common developing late clinical signs were those of aggression towards other dogs and urinary and fecal incontinence as a result of loss of house training (disinhibited). The https:// ensures that you are connecting to the LD has also been reported in other species including a Fennec fox [16], cows [17] and possibly a parakeet [18]. With the development of the genetic database it should become easier to identify the risk to each individual animal and eventually eliminate LD from the UK MWHD population. Mere 50% reduction of glycogen synthase activity in LD mouse models through transgenic approaches was shown to eliminate LB and the neurological phenotype of the disease [5, 2123]. Mice (our unpublished observation) and humans [41] in whom this has been tried maintain physiological blood glucose levels and generate just as profuse LB as with normal diet. An official website of the United States government. For any MWHD suffering with progressive myoclonus or seizure activity treatment with anti-epileptics should be initiated promptly. (c) Transverse T2W at level of occipital lobes demonstrating cortical atrophy with widening of the subarachnoid space (green arrow) and enlargement of the lateral ventricle (orange arrow). Non-pathogenic polyglucosan bodies occur as an aging-related change in many species including cats, dogs and man. Finally there was a question about possible comorbidities including previous diagnosis of intervertebral disease. Magnetic resonance imaging (MRI) may reveal generalized cortical atrophy with ventriculomegaly (Fig 1) [1, 9]. Yes by using low carbohydrate diets such as the ketogenic diet. Holland JM, Davis WC, Prieur DJ, Collins GH. Conceptualization, The remaining 11 dogs were not tested as they died prior to the genetic test being available. In some cases where dogs suffer greatly from photosensitive myoclonus the use of canine specific sun goggles have been used to limit clinical signs. Ianzano L, Zhang J, Chan EM, Zhao XC, Lohi H, Scherer SW, et al. Both dogs have spontaneous and reflex myoclonic jerks with an intention tremor. Myoclonus, in particular, becomes progressively more severe although anecdotally there is an initial response to levetiracetum. Needle electromyography (EMG) has been reported to show abnormal spontaneous activity of the muscles with positive sharp waves and fibrillation potential [8]. The mean age of onset of clinical signs was 6.94 years which correlated with the median age of onset of 7 years. Lafora disease (progressive myoclonic epilepsy) in the Bassett houndpossibility of early diagnosis using muscle biopsy? (c) Transverse T2W at level of occipital lobes demonstrating cortical atrophy with widening of the subarachnoid space (green arrow) and enlargement of the lateral ventricle (orange arrow). Hulsmeyer VI, Fischer A, Mandigers PJ, DeRisio L, Berendt M, Rusbridge C, et al. In particular, clinically affected dogs presented to veterinary surgeons are less likely to be tested. Clinical trials require detailed description of the clinical disease and its natural progression. All dogs that tested negative for LD were also excluded. Anecdotally, leviteracetam was found to be particularly effective in reducing myoclonus in early disease. Fitzpatrick Referrals Ltd, provided support in the form of salaries and materials for authors LS, AT and CR. PLOS ONE promises fair, rigorous peer review, With the development of the genetic database it should become easier to identify the risk to each individual animal and eventually eliminate LD from the UK MWHD population. Participants were also asked their opinion on the impact of LD on daily living. Lafora disease (LD) is an autosomal recessive myoclonic epilepsy caused by mutations in the EPM2A gene, encoding the glycogen phosphatase laforin, or the EPM2B gene coding the ubiquitin E3 ligase malin [13]. Genetic testing is not routinely available because the massive dodecamer repeat expansion mutation makes PCR-based sequencing options unreliable for detecting the carrier state and consequently only a southern blot based test is offered by the University of Toronto and is an official DNA screening test recommended by the UK Kennel Club (Fig 2). Neuronal somatodendritic polyglucosan bodies in young animals or humans are essentially pathognomonic of LD. The genetic test is Southern blotting based [12], because PCR-based sequencing options through the massive dodecamer repeat expansion mutation have so far proven inadequately reliable. Yes Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada, Roles GK is a member of the Lafora disease Subcommittee which is part of the Dachshund Breed Council affiliated with the UK Kennel Club. In these cases, the polyglucosan bodies are present not in the somatodendritic compartments of neurons, but in their axons or axon hillocks, leading not to an epileptic condition but to an axonopathy resembling amyotrophic lateral sclerosis. To improve survey accuracy technical terms were explained within the survey for example generalized seizures were explained as also known as grand mal or tonic clonic and characterized by initial stiffening of the limbs followed by jerking of the limbs and face. They are an important consideration in canine LD, because in this species the disease is late in onset and brain necropsies could be misconstrued as representing LD in aged dogs [3339]. Much smaller LBs are located throughout (small arrows). All dogs that tested negative for LD were also excluded. 1 broad scope, and wide readership a perfect fit for your research every time. Resources, Both dogs have spontaneous and reflex myoclonic jerks with an intention tremor. All these clinical signs may appear, and then increase in frequency and intensity over time. LD, in this sense, can be regarded as a canine genome particular disease, and is likely to continue to be seen in different purebred breeds with each recurrence of the expansion mutation. Further prospective study is needed to further characterize the canine disease and to allow more specific therapeutic strategies and to tailor therapy as the disease progresses. For any MWHD suffering with progressive myoclonus or seizure activity treatment with anti-epileptics should be initiated promptly. In work recently published in abstract form, antisense oligonucleotides targeting glycogen synthase eliminated Lafora bodies in LD mouse models, establishing proof of principle for this strategy [43]. Key G. Survey Results Autumn 2012 2012 [cited 2016 April 16th]. Average age of onset of clinical signs was 6.94 years (3.512). Writing original draft, 8600 Rockville Pike Bar equals 50m. 327802) partially subsidized the cost of genetic testing of many of the dogs in this study. The .gov means its official. The remaining 11 dogs were not tested as they died prior to the genetic test being available. Bar equals 50m. To improve survey accuracy technical terms were explained within the survey for example generalized seizures were explained as also known as grand mal or tonic clonic and characterized by initial stiffening of the limbs followed by jerking of the limbs and face. The genetic work was part funded by the Ontario Brain Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award number P01 NS097197. Its early signs are myoclonus and generalized tonic-clonic seizures, along with transient blindness, visual hallucinations (often with frightening content) or photoconvulsions. https://doi.org/10.1371/journal.pone.0182024.s001, https://doi.org/10.1371/journal.pone.0182024.s002. The precise roles of the Epm2a and Epm2b genes remain unknown. Ethics committee approval for this project was not sought because the decision to create and run the survey was made by the Lafora disease subcommittee (part of the Dachshund Breed Council) and ethics approval cannot be made retrospectively. Funding: The Kennel Club Charitable Trust registered charity (No. disinhibited behavior (both fecal and urinary), jaw smacking and fly catching however the survey did not include data on how this disease progressed. 2nd Biennial International Lafora workshop in 23rd -24th June 2016; Sanford Consortium for Regenerative Medicine, La Jolla, California. Our study showed that LD in the MWHD is a progressive myoclonic epilepsy similar to the disease process in humans. Investigation, Other common signs were generalized tonic clonic seizures, hypnic myoclonus, panic attacks and dementia. Investigation, This retrospective study was based on the analysis of responses to a confidential online survey which did not collect personal data and no aspect comes under the auspices of Animals (Scientific Procedures) Act 1986. Bar equals 500nm. However, all treatment is anecdotal as no research has been performed to assess the efficacy of individual therapies. SA, PW, CA and BM are employed by the Hospital for Sick Children, University of Toronto. The survey participant was asked to enter the dogs age that they first noticed the clinical signs or never if this sign was not noticed. Webb AA, McMillan C, Cullen CL, Boston SE, Turnbull J, Minassian BA. The remaining clinical signs at presentation were fly catching and panic attacks, focal seizures, aggression toward people, urinary incontinence as a result of loss of house training, poor vision or blindness, fecal incontinence, or dementia. In human or canine LD, polyglcuosan bodies are also seen in various tissues outside the brain, such as muscle, heart and liver, but in these organs, they appear to be clinically neutral, usually the patient succumbing to the neurological disease without ever having developed clinical signs of hepatic, cardiac or skeletal muscle disease. Resources, It is possible that the dogs do not develop more severe signs because they would die of natural causes first [1]. The_Kennel_Club. Journal of veterinary diagnostic investigation: official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. Lafora bodies in the retina of various animals, Polyglucosan bodies in the digestive tract of the aged dog, Lafora-like inclusion bodies in the CNS of aged dogs, Topographic distribution pattern of Lafora-like bodies in the spinal cord of some animals, Correlative studies of axonal spheroids and Lafora-like bodies in aged dogs. Click through the PLOS taxonomy to find articles in your field. Much smaller LBs are located throughout (small arrows). Precisely how the laforin-malin partner enzymes regulate glycogen structure remains unclear [19, 20]. It is most frequent in Miniature Wirehaired Dachshunds (MWHD) [1, 8, 9], Bassett Hounds [1, 10] and Beagles [11, 12], and single cases have been reported in the Miniature and Standard Poodle [13], Pointer [14], and a Corgi [15]. As the disease progresses clinical signs become more intense and often dogs may be euthanized due to their severity. Ethics committee approval for this project was not sought because the decision to create and run the survey was made by the Lafora disease subcommittee (part of the Dachshund Breed Council) and ethics approval cannot be made retrospectively. Yamanami S, Ishihara T, Takahashi M, Uchino F. Comparative study of intraneuronal polyglucosan bodies in brains from patients with Lafora disease and aged dogs, Zonisamide for progressive myoclonus epilepsy: long-term observations in seven patients. PMC legacy view Phenotype variations in Lafora progressive myoclonus epilepsy: possible involvement of genetic modifiers? A detailed canine natural progression study will allow organization of clinical trials also in dogs. In human patients suffering from LD hallucinations occur regularly, causing anxiety. As the disease progresses the severity, frequency and refractoriness of the seizures increase. Investigation, Less frequent clinical signs are illustrated in Table 3, Distribution of clinical signs in the LD affected and suspected dogs after 13 years of disease. The range of the onset of clinical signs was wide at 3.5 to 12 years. Lafora's disease in the dog. Turnbull J, Tiberia E, Striano P, Genton P, Carpenter S, Ackerley CA, et al. Signs that developed later in the disease include dementia (51.9%), blindness (48.1%), aggression to people (25.9%) and dogs (33.3%), deafness (29.6%) and fecal (29.6%) and urinary (37.0%) incontinence as a result of loss of house training (disinhibited type behavior). Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada, 4 It is most frequent in Miniature Wirehaired Dachshunds (MWHD) [1, 8, 9], Bassett Hounds [1, 10] and Beagles [11, 12], and single cases have been reported in the Miniature and Standard Poodle [13], Pointer [14], and a Corgi [15]. Writing review & editing, Affiliation As such a larger amount of DNA is required than can be obtained from cheek swabs, and generally a blood sample is used. Work is very much underway to identify small molecule or other glycogen synthesis inhibitors to achieve 50% reduction in brain glycogen synthesis. No, Is the Subject Area "Myoclonus" applicable to this article? The genetic test is Southern blotting based [12], because PCR-based sequencing options through the massive dodecamer repeat expansion mutation have so far proven inadequately reliable. Non-pathogenic polyglucosan bodies occur as an aging-related change in many species including cats, dogs and man. The genetic work was part funded by the Ontario Brain Institute and the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NIH) under award number P01 NS097197. Its early signs are myoclonus and generalized tonic-clonic seizures, along with transient blindness, visual hallucinations (often with frightening content) or photoconvulsions. Current therapy for LD is aimed at limiting clinical signs of the disease. What is clear is that the former encodes a phosphatase (laforin) that regulates a small but important amount of phosphate covalently bound to glycogen. All, however, had the classical clinical disease including spontaneous and reflex myoclonic jerks. Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E, et al. Informed written consent to use data was obtained from survey participants. about navigating our updated article layout. Distribution of clinical signs in the LD affected and suspected dogs at presentation, In the gene test-positive group the most frequent new clinical sign that developed over the first 13 years following presentation was poor vision /blindness which was reported in over one third of the dogs. Hajek I, Kettner F, Simerdova V, Rusbridge C, Wang P, Minassian BA, et al. Honnold SP, Schulman FY, Bauman K, Nelson K. Lafora's-like disease in a fennec fox (Vulpes zerda), A storage disease in a parakeet (Nymphicus hollandicus) morphologically similar to the systemic myoclonic disease (Lafora disease) in man and dog, Zentralblatt fur Veterinarmedizin Reihe A. Gayarre J, Duran-Trio L, Criado Garcia O, Aguado C, Juana-Lopez L, Crespo I, et al. Table 2 illustrates the distribution of fourteen common clinical signs at presentation in LD for both mutation-positive and untested cases. 2016. p. 15. http://laforadogs.org/surveys/interim-survey-results-autumn-2012, https://sites.google.com/site/ukdachshundhealthreport/dachshund-health-resources/lafora-disease, http://www.thekennelclub.org.uk/health/breeding-for-health/dna-screening-schemes-and-results/dna-screening-for-breeds-c-g/dachshund-(miniature-wire-haired)-dna-screening/. As the disease progresses the severity, frequency and refractoriness of the seizures increase. Dachshund (Miniature Wire Haired) DNA screening 2016 [cited 2016 April 16th]. The most common sign for both were reflex and spontaneous myoclonus, hypnic myoclonus, generalized seizures, and jaw smacking. Owners described the (presumed) panic attacks as particularly distressing and from the description [24] we hypothesize that the dogs may be experiencing frightening visual hallucinations as the dogs behavior suggested fear and an escape response. Gradual precipitation, aggregation, and accumulation of polyglucosans results in massive neurotoxic inclusions (Lafora bodies; LB), which drive the neurodegenerative epilepsy [3] (Fig 3). The most common sign for both were reflex and spontaneous myoclonus, hypnic myoclonus, generalized seizures, and jaw smacking. Recent breed-wide testing suggests that the carrier plus affected rate may be as high as 20%. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript with the exception of the Dachshund Breed Council which has a Health and Welfare subcommittee which instigated the data collection but did not play a role in analysis. Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Canada, 5 Fitzpatrick Referrals Ltd, provided support in the form of salaries and materials for authors LS, AT and CR. The precise roles of the Epm2a and Epm2b genes remain unknown. As such a larger amount of DNA is required than can be obtained from cheek swabs, and generally a blood sample is used. Clinical signs are similar to those of the human disease, including spontaneous and reflex myoclonus, hypnic jerks and generalized tonic clonic seizures [1]. Common signs of disease were identified: myoclonic jerks (spontaneous and reflex, most commonly induced by light, sound or sudden movement in the visual field), hypnic myoclonus (twitch as falling asleep), seizures (both focal and tonic-clonic), ataxia, poor vision/blindness, deafness, dementia (defined as a behavior change suggesting disorientation and memory loss with or without altered sleep wake cycle and anxiety), aggression (toward people and other dogs), incontinence due to loss of house training i.e. Both are mutation positive for LD. disinhibition and a specific sign of senility) or was more likely due to other causes. B. Electron micrograph of a LB in the terminal cytoplasm of a dendrite. Which proteins are the precise target(s) of malin remains unknown, but absence of malins function, like absence of laforin, leads to poorly branched and insoluble glycogen (polyglucosans), which accumulate in neuronal somatodendritic compartments into Lafora bodies (polyglucosan bodies), over time driving the neurodegeneration and progressive myoclonic epilepsy[28] (Fig 3). A characteristic feature of the disease is spontaneous and reflex myoclonus; however clinical signs and disease progression are not well described. No, Is the Subject Area "Mutation" applicable to this article? For more information about PLOS Subject Areas, click Visualization, Based on data published by the UK Kennel Club the frequency of carriers (34%) and genetically affected dogs (6%) is high [27] although this figure does not include hereditary clear dogs and the estimated carrier and affected rate may be closer to 20% (Ian Seath, personal communication). Yes Survey responses were excluded if the dogs were not UK bred MWHD or were mutation positive and not yet showing clinical signs. Visualization, Lafora progressive Myoclonus Epilepsy mutation database-EPM2A and NHLRC1 (EPM2B) genes, Lafora's disease: towards a clinical, pathologic, and molecular synthesis. International Veterinary Epilepsy Task Force's current understanding of idiopathic epilepsy of genetic or suspected genetic origin in purebred dogs, Polyglucosan storage disease in a dog resembling Lafora's disease, Journal of veterinary internal medicine / American College of Veterinary Internal Medicine. Rusbridge C, Fitzmaurice SN, Lohi H, Young EJ, Minassian BA. Current therapy for LD is aimed at limiting clinical signs of the disease. There was also open questions to allow participants to enter other clinical signs and other comments. A genetic database of MWHD bred in the United Kingdom aimed at identifying affected and carrier animals was established by the Dachshund Breed Council [25]. Cardinali S, Canafoglia L, Bertoli S, Franceschetti S, Lanzi G, Tagliabue A, et al. Owners described the (presumed) panic attacks as particularly distressing and from the description [24] we hypothesize that the dogs may be experiencing frightening visual hallucinations as the dogs behavior suggested fear and an escape response. Conceptualization, Formal analysis, Mere 50% reduction of glycogen synthase activity in LD mouse models through transgenic approaches was shown to eliminate LB and the neurological phenotype of the disease [5, 2123]. Precisely how the laforin-malin partner enzymes regulate glycogen structure remains unclear [19, 20]. All affected dogs to date, from all breeds, have the same expansion mutation in the Epm2b dodecamer repeat unique to the canid orthologue of the gene. Fourteen dogs were immediately excluded from the study as they were not showing clinical signs at the time of the study; four of these dogs had tested positive for the LD disease mutation but did not yet show clinical signs (all these dogs were younger than the age of onset of canine LD). Project administration, Duran J, Gruart A, Garcia-Rocha M, Delgado-Garcia JM, Guinovart JJ. Although the presence of hallucinations in the canine disease can neither be confirmed nor denied, the use of anxiolyitcs, such as alprazolam, are potentially beneficial in dogs with LD. The Kennel Club Charitable Trust registered charity (No. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Canada, This is the most common neurological disease in this breed which could be alternative cause of the clinical sign of ataxia. Consequently, in 2013 the online survey was refined to include information about age of onset, progression of clinical signs, comorbidities, impact of disease and, if applicable, age of death (S1 Text) [26]. Roles https://doi.org/10.1371/journal.pone.0182024.s003. Lafora disease (LD) is an autosomal recessive myoclonic epilepsy caused by mutations in the EPM2A gene, encoding the glycogen phosphatase laforin, or the EPM2B gene coding the ubiquitin E3 ligase malin [13]. Common signs of disease were identified: myoclonic jerks (spontaneous and reflex, most commonly induced by light, sound or sudden movement in the visual field), hypnic myoclonus (twitch as falling asleep), seizures (both focal and tonic-clonic), ataxia, poor vision/blindness, deafness, dementia (defined as a behavior change suggesting disorientation and memory loss with or without altered sleep wake cycle and anxiety), aggression (toward people and other dogs), incontinence due to loss of house training i.e. One of these is the LD Subcommittee which constructed an online survey in 2012 with the aim of assessing the clinical signs and impact of LD [24, 25]. No, Is the Subject Area "Reflexes" applicable to this article? Distribution of clinical signs in the LD affected and suspected dogs after 3 years of disease. PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. The Dachshund Breed Council is affiliated with the UK Kennel Club and represents the interests of sixteen UK Dachshund Breed Clubs and appoints Health and Welfare Sub-committees to develop policies and coordinate plans for Dachshund breed health improvement. The myoclonus in particular becomes more severe and more refractory to treatment. The Dachshund Breed Council represents the interests of sixteen UK Dachshund Breed Clubs and appoints Health and Welfare Sub-committees to develop policies and coordinate plans for Dachshund breed health improvement. Participants were invited if they had previously contacted the MWHD Lafora subcommittee about pets with clinical signs of LD and/or if they had participated in bi-annual bulk genetic testing for LD through the Dachshund Breed Council [25]. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For this reason, the test is still not available through a commercial laboratory. Table 2 illustrates the distribution of fourteen common clinical signs at presentation in LD for both mutation-positive and untested cases. Unlike in humans, LD affected MWHD do not enter a vegetative state in constant myoclonus. 327802) partially subsidized the cost of genetic testing of many of the dogs in this study. Other common signs were generalized tonic clonic seizures, hypnic myoclonus, panic attacks and dementia. e0182024. Antisense oligonucleotide therapy for the fatal epilepsy Lafora disease. Discover a faster, simpler path to publishing in a high-quality journal. This retrospective study was based on the analysis of responses to a confidential online survey which did not collect personal data and no aspect comes under the auspices of Animals (Scientific Procedures) Act 1986. School of Veterinary Medicine, Faculty of Health & Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom. Turnbull J, Epp JR, Goldsmith D, Zhao X, Pencea N, Wang P, et al. Notwithstanding, a shortcut to therapy was recently suggested. Complete blood count, serum biochemistry, urinalysis and cerebrospinal fluid are normal [8, 9]. (2017) Lafora disease in miniature Wirehaired Dachshunds. https://doi.org/10.1371/journal.pone.0182024.g002. Electroencephalographic (EEG) measurements reveal bilateral synchronous polyspike-wave paroxysms and erratic myoclonus without EEG correlation [11]. Late onset clinical signs (those developing 3 years or more after initial presentation) in the mutation-positive group were dementia followed by panic attacks, urinary incontinence, and deafness (Table 4).

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