ABSTRACT
Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.
Subject(s)
Autophagy/genetics , Cysteine Endopeptidases/genetics , Mutation, Missense , Neurodegenerative Diseases/genetics , Vacuoles/metabolism , Amino Acid Sequence , Animals , Base Sequence , Brain/metabolism , Brain/pathology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Dogs , Molecular Sequence Data , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/veterinary , Vacuoles/genetics , ZebrafishABSTRACT
A missense variant in the autophagy-related ATG4D-gene has been associated with a progressive degenerative neurological disease in Lagotto Romagnolo (LR) dogs. In addition to neural lesions, affected dogs show an extraneural histopathological phenotype characterized by severe cytoplasmic vacuolization, a finding not previously linked with disturbed autophagy in animals. Here we aimed at testing the hypothesis that autophagy is altered in the affected dogs, at reporting the histopathology of extraneural tissues and at excluding lysosomal storage diseases. Basal and starvation-induced autophagy were monitored by Western blotting and immunofluorescence of microtubule associated protein 1A/B light chain3 (LC3) in fibroblasts from 2 affected dogs. The extraneural findings of 9 euthanized LRs and skin biopsies from 4 living affected LRs were examined by light microscopy, electron microscopy, and immunohistochemistry (IHC), using antibodies against autophagosomal membranes (LC3), autophagic cargo (p62), and lysosomal membranes (LAMP2). Biochemical screening of urine and fibroblasts of 2 affected dogs was performed. Under basal conditions, the affected fibroblasts contained significantly more LC3-II and LC3-positive vesicles than did the controls. Morphologically, several cells, including serous secretory epithelium, endothelial cells, pericytes, plasma cells, and macrophages, contained cytoplasmic vacuoles with an ultrastructure resembling enlarged amphisomes, endosomes, or multivesicular bodies. IHC showed strong membranous LAMP2 positivity only in sweat glands. The results show that basal but not induced autophagy is altered in affected fibroblasts. The ultrastructure of affected cells is compatible with altered autophagic and endo-lysosomal vesicular traffic. The findings in this spontaneous disease provide insight into possible tissue-specific roles of basal autophagy.
Subject(s)
Autophagy-Related Proteins/genetics , Autophagy/genetics , Cysteine Endopeptidases/genetics , Lysosomal Storage Diseases/veterinary , Neurodegenerative Diseases/veterinary , Animals , Blotting, Western/veterinary , Cytoplasm/pathology , Dogs , Female , Fluorescent Antibody Technique/veterinary , Immunohistochemistry/veterinary , Lysosomal Storage Diseases/genetics , Lysosomal Storage Diseases/pathology , Lysosomes/pathology , Male , Microscopy, Electron/veterinary , Mutation, Missense , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Vacuoles/pathologyABSTRACT
Small brachycephalic dog breeds, such as the French bulldog, English bulldog and pug have become increasingly popular. These breeds are predisposed to a variety of vertebral and spinal malformations, including hemivertebra, caudal articular process dysplasia, transitional vertebra, cranial thoracic vertebral canal stenosis, spinal arachnoid diverticulum and meningeal fibrosis. Recent studies have provided new insights into the prevalence, anatomical characteristics, pathophysiology and treatment of these conditions. Thoracic hemivertebra, caudal articular process dysplasia, transitional vertebra, and cranial thoracic vertebral canal stenosis occur commonly in neurologically normal dogs. Although the clinical relevance of these vertebral anomalies has therefore been questioned, severe kyphosis and hemivertebra in pugs have been associated with an increased likelihood of neurological signs. Meningeal fibrosis is characterised by the formation of dense intradural fibrotic adhesions, constricting the spinal cord. This condition has been heavily associated with the pug breed. It is in pugs further common to observe multiple concurrent spinal disorder in association with chronic progressive pelvic limb gait abnormalities. This clinical presentation has been referred to as 'pug dog thoracolumbar myelopathy' and potential genetic risk factors have recently been identified. Despite our increased knowledge, many questions remain currently unanswered. This review discusses our current understanding and controversies surrounding vertebral and spinal malformations in small brachycephalic dog breeds.
Subject(s)
Craniosynostoses , Dog Diseases , Spinal Cord Diseases , Dogs , Animals , Dog Diseases/epidemiology , Spine , Spinal Cord Diseases/veterinary , Craniosynostoses/genetics , Craniosynostoses/veterinary , FibrosisABSTRACT
BACKGROUND: Pugs commonly present with thoracolumbar myelopathy, also known as pug dog myelopathy (PDM), which is clinically characterised by progressive signs involving the pelvic limbs, no apparent signs of pain and, often, incontinence. In addition to meningeal fibrosis and focal spinal cord destruction, histopathology has confirmed lymphohistiocytic infiltrates in the central nervous system (CNS) in a considerable number of pugs with PDM. Lymphohistiocytic CNS inflammation also characterises necrotising meningoencephalitis (NME) in pugs. This study aimed to investigate the potential contribution of an immunological aetiology to the development of PDM. METHODS: The concentrations of glial fibrillary acidic protein (GFAP) in serum and CSF and of anti-GFAP autoantibodies in CSF were measured with an ELISA. In addition, a commercial test was used for genetic characterisation of the dog leukocyte antigen class II haplotype, which is associated with NME susceptibility. RESULTS: This study included 87 dogs: 52 PDM pugs, 14 control pugs, four NME pugs and 17 dogs of breeds other than pugs that were investigated for neurological disease (neuro controls). Anti-GFAP autoantibodies were present in 15 of 19 (79%) of the PDM pugs tested versus six of 16 (38%) of the neuro controls tested (p = 0.018). All 18 PDM pugs evaluated had detectable CSF GFAP. Serum GFAP was detected in two of three (67%) of the NME pugs and in two of 11 (18%) of the control pugs but not in any of the 40 tested PDM pugs. Male pugs heterozygous for the NME risk haplotype had an earlier onset of clinical signs (70 months) compared to male pugs without the risk haplotype (78 months) (p = 0.036). LIMITATIONS: The study was limited by the lack of healthy dogs of breeds other than pugs and the small numbers of control pugs and pugs with NME. CONCLUSIONS: The high proportion of PDM pugs with anti-GFAP autoantibodies and high CSF GFAP concentrations provide support for a potential immunological contribution to the development of PDM.
Subject(s)
Autoantibodies , Dog Diseases , Glial Fibrillary Acidic Protein , Meningoencephalitis , Spinal Cord Diseases , Animals , Dogs , Dog Diseases/genetics , Dog Diseases/immunology , Meningoencephalitis/veterinary , Meningoencephalitis/genetics , Meningoencephalitis/immunology , Autoantibodies/blood , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/immunology , Male , Spinal Cord Diseases/veterinary , Spinal Cord Diseases/genetics , Female , Genotype , Genetic Predisposition to DiseaseABSTRACT
Pug dogs with thoracolumbar myelopathy (PDM) present with a specific clinical phenotype that includes progressive pelvic limb ataxia and paresis, commonly accompanied by incontinence. Vertebral column malformations and lesions, excessive scar tissue of the meninges, and central nervous system inflammation have been described. PDM has a late onset and affects more male than female dogs. The breed-specific presentation of the disorder suggests that genetic risk factors are involved in the disease development. To perform a genome-wide search for PDM-associated loci, we applied a Bayesian model adapted for mapping complex traits (BayesR) and a cross-population extended haplotype homozygosity test (XP-EHH) in 51 affected and 38 control pugs. Nineteen associated loci (harboring 67 genes in total, including 34 potential candidate genes) and three candidate regions under selection (with four genes within or next to the signal) were identified. The multiple candidate genes identified have implicated functions in bone homeostasis, fibrotic scar tissue, inflammatory responses, or the formation, regulation, and differentiation of cartilage, suggesting the potential relevance of these processes to the pathogenesis of PDM.
Subject(s)
Bone Diseases, Developmental , Spinal Cord Diseases , Animals , Dogs , Male , Female , Cicatrix , Bayes Theorem , Spinal Cord Diseases/veterinary , Thoracic Vertebrae , Genetic LociABSTRACT
Rickets is a disorder of bone development and can be the result of either dietary or genetic causes. Here, related pugs from 2 litters were included. Three pugs had clinical signs including, lameness, bone deformities, and dyspnea. One other pug was found dead. Radiographs of 2 affected pugs, 5 and 6 months old, showed generalized widening, and irregular margination of the physes of both the appendicular and the axial skeleton with generalized decrease in bone opacity and bulbous swelling of the costochondral junctions. Two pugs had low serum calcium and 1,25 (OH)2 D3 concentrations. Test results further indicated secondary hyperparathyroidism with adequate concentrations of 25-hydroxyvitamin D. Necropsy revealed tongue-like projections of cartilage extending into the metaphysis consistent with rickets, loss of metaphyseal mineralization and lung pathology. Vitamin D-dependent rickets was diagnosed. A truncating mutation in the 1α-hydroxylase gene (CYP27B1) was identified by genome sequence analysis of the pugs with VDDR type 1A. Vitamin D-dependent rickets type 1A can occur in young pugs, and if left untreated is a life-threatening condition. Early medical intervention can reverse clinical signs and should be instituted as soon as possible.
Subject(s)
25-Hydroxyvitamin D3 1-alpha-Hydroxylase , Rickets , Animals , 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics , Rickets/genetics , Rickets/veterinary , Vitamin D , Mutation , DietABSTRACT
'Staggering disease' is a neurological disease entity considered a threat to European domestic cats (Felis catus) for almost five decades. However, its aetiology has remained obscure. Rustrela virus (RusV), a relative of rubella virus, has recently been shown to be associated with encephalitis in a broad range of mammalian hosts. Here, we report the detection of RusV RNA and antigen by metagenomic sequencing, RT-qPCR, in-situ hybridization and immunohistochemistry in brain tissues of 27 out of 29 cats with non-suppurative meningoencephalomyelitis and clinical signs compatible with'staggering disease' from Sweden, Austria, and Germany, but not in non-affected control cats. Screening of possible reservoir hosts in Sweden revealed RusV infection in wood mice (Apodemus sylvaticus). Our work indicates that RusV is the long-sought cause of feline 'staggering disease'. Given its reported broad host spectrum and considerable geographic range, RusV may be the aetiological agent of neuropathologies in further mammals, possibly even including humans.
Subject(s)
Encephalomyelitis , Humans , Animals , Cats , Mice , Causality , Sweden , Austria , Germany , MammalsABSTRACT
OBJECTIVES: The primary objective of this study was to investigate the prevalence of epileptic seizures and of presumed idiopathic epilepsy (PIE, describing epilepsy of unknown origin) in a cohort of British Shorthair (BSH) cats in Sweden. The secondary objective was to describe epileptic seizure characteristics and outcome for cats with PIE. METHODS: Owners of BSH cats born between 2006 and 2016 and registered with SVERAK (the Swedish Cat Clubs' National Association) were invited to reply to a questionnaire about their cat's general health. Owners who indicated that their cat had experienced epileptic seizures were invited to participate in an in-depth telephone interview about the epileptic seizures. The clinical characteristics of epileptic seizures in BSH cats were determined from the results of the interview. RESULTS: In this population comprising 1645 BSH cats (representing 28% of registered BSHs), the prevalence of epileptic seizures was 0.9% and for PIE it was 0.7%. BSH cats with PIE presented with infrequent but consistent epileptic seizures. Twenty-seven percent of BSH cats with epileptic seizures had cluster seizures but none presented with status epilepticus. None of the BSH cats was treated with antiepileptic drugs, and none of the owners reported epileptic seizure remission in their cat. CONCLUSIONS AND RELEVANCE: The prevalence of PIE in this population of BSH cats was 0.7%. The prevalence of epileptic seizures was 0.9%. In general, PIE in the BSH cat displayed a relatively benign phenotype where progression of epileptic seizures was uncommon.
Subject(s)
Cat Diseases , Epilepsy , Animals , Anticonvulsants/therapeutic use , Cat Diseases/drug therapy , Cat Diseases/epidemiology , Cats , Cohort Studies , Epilepsy/drug therapy , Epilepsy/epidemiology , Epilepsy/veterinary , Humans , Seizures/drug therapy , Seizures/epidemiology , Seizures/veterinary , Sweden/epidemiologyABSTRACT
Tick-borne encephalitis (TBE) is caused by the neurotropic tick-borne encephalitis virus (TBEV). In dogs, this virus may affect the central nervous system (CNS), causing meningoencephalitis, meningomyelitis, radiculitis or any combination of these. Diagnosis of TBE relies on a combination of clinical signs of CNS disease and laboratory findings, including CSF pleocytosis and serum TBEV antibody titers. Exposure to TBEV does not necessarily cause clinical disease, and seroprevalence has been reported as high as 40% in endemic areas. This causes concerns of over-diagnosing TBE in dogs with CNS disease. By examining TBEV antibodies in dogs with and without neurological disease in a TBEV endemic area, this study aimed to evaluate the diagnostic value of TBEV antibodies in the cerebrospinal fluid (CSF) in dogs. Eighty-nine dogs were included in the study, 56 with neurological disease and 33 neurologically normal control dogs. A positive TBEV CSF and serum IgG antibody titer (> 126 U/mL) was found in 3/89 dogs (3.4%). A positive serum TBEV antibody titer was found in 11 of the 89 dogs (12.4%). None of the control dogs showed a positive CSF antibody titer, whilst two showed positive serum concentrations. A positive CSF IgG antibody titer supports a clinical diagnosis of TBE in patients with acute onset of CNS disease and may help reduce the risk of over-diagnosis.
Subject(s)
Dog Diseases , Encephalitis Viruses, Tick-Borne , Encephalitis, Tick-Borne , Animals , Antibodies, Viral , Dog Diseases/diagnosis , Dogs , Encephalitis, Tick-Borne/diagnosis , Encephalitis, Tick-Borne/veterinary , Immunoglobulin G , Seroepidemiologic StudiesABSTRACT
Mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause degenerative polyneuropathy in ways that are poorly understood. We have investigated Alaskan Malamute dogs with neuropathy caused by a missense mutation in NDRG1. In affected animals, nerve levels of NDRG1 protein were reduced by more than 70% (p< 0.03). Nerve fibers were thinly myelinated, loss of large myelinated fibers was pronounced and teased fiber preparations showed both demyelination and remyelination. Inclusions of filamentous material containing actin were present in adaxonal Schwann cell cytoplasm and Schmidt-Lanterman clefts. This condition strongly resembles the human Charcot-Marie-Tooth type 4D. However, the focally folded myelin with adaxonal infoldings segregating the axon found in this study are ultrastructural changes not described in the human disease. Furthermore, lipidomic analysis revealed a profound loss of peripheral nerve lipids. Our data suggest that the low levels of mutant NDRG1 is insufficient to support Schwann cells in maintaining myelin homeostasis.
Subject(s)
Cell Cycle Proteins , Charcot-Marie-Tooth Disease/veterinary , Dog Diseases/genetics , Intracellular Signaling Peptides and Proteins , Schwann Cells/metabolism , Animals , Charcot-Marie-Tooth Disease/genetics , Dogs , Female , Male , Mutation/genetics , Mutation, Missense , Myelin Sheath , Polyneuropathies/geneticsABSTRACT
BACKGROUND: Thoracolumbar myelopathies associated with spinal cord and vertebral column lesions, with a similar clinical phenotype, but different underlying etiologies, occur in pugs. OBJECTIVES: To further characterize the clinical and neuropathological characteristics of pugs with longstanding thoracolumbar myelopathy. ANIMALS: Thirty client-owned pure-bred pugs with a history of more than a month of ataxia and paresis of the pelvic limbs, suggesting a myelopathy localized to the thoracolumbar spinal cord, were included in the study. METHODS: Prospective clinicopathological study. Included pugs underwent a complete neurological examination and gross and histopathologic postmortem studies with focus on the spinal cord. Computed tomography (n = 18), magnetic resonance imaging (n = 17), and cerebrospinal fluid analysis (n = 27) were performed before or immediately after death. RESULTS: Twenty male and 10 female pugs had a median age at clinical onset of 84 months (interquartile range, 66-96). Affected pugs presented with a progressive clinical course and 80% were incontinent. There was circumferential meningeal fibrosis with concomitant focal, malacic, destruction of the neuroparenchyma in the thoracolumbar spinal cord in 24/30 pugs. Vertebral lesions accompanied the focal spinal cord lesion, and there was lympho-histiocytic inflammation associated or not to the parenchymal lesion in 43% of the pugs. CONCLUSIONS AND CLINICAL IMPORTANCE: Meningeal fibrosis with associated focal spinal cord destruction and neighboring vertebral column lesions were common findings in pugs with long-standing thoracolumbar myelopathy.
Subject(s)
Dog Diseases/diagnosis , Fibrosis/veterinary , Spinal Cord Compression/veterinary , Thoracic Vertebrae , Animals , Dog Diseases/cerebrospinal fluid , Dog Diseases/diagnostic imaging , Dogs , Female , Fibrosis/diagnosis , Magnetic Resonance Imaging/veterinary , Male , Neurologic Examination/veterinary , Pedigree , Prospective Studies , Spinal Cord Compression/diagnosis , Tomography, X-Ray Computed/veterinaryABSTRACT
BACKGROUND: Although thoracic hemivertebra can cause neurological signs, they occur commonly in neurologically normal dogs. OBJECTIVES: To evaluate whether computed tomography (CT) findings and factors associated with signalment can be used to differentiate between dogs with and without neurological signs associated with hemivertebra. ANIMALS: One hundred sixty dogs with ≥1 hemivertebrae were retrospectively studied. This group consisted of 40 dogs with clinical signs caused by hemivertebra and 40 French Bulldogs, 40 Pugs, and 40 English Bulldogs that underwent CT for reasons unrelated to neurological disease. METHODS: All dogs underwent CT and affected dogs also underwent magnetic resonance imaging. All CT studies were randomly evaluated by an observer blinded to signalment and clinical status. The following variables were evaluated: presence, number, location, and subtype of hemivertebra; presence of vertebral subluxation; severity of vertebral canal stenosis; presence, location, and severity of kyphosis, and number of vertebrae involved in the kyphotic segment. Statistical modeling was performed to identify factors associated with clinical status. RESULTS: Pug breed (odds ration [OR], 10.8; P = .01), more severe kyphosis (OR, 1.1 per grade increase; P < .001), fewer instead of more observed hemivertebrae (OR, 0.8; P = 0.03), and ventrolateral hypoplasia hemivertebra subtype (OR, 4.0; P = .011) were associated with higher likelihood of neurological disease. A Cobb angle of 34.5 degrees corresponded with the highest combined sensitivity and specificity to differentiate between clinically affected and unaffected dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: The variables identified could aid in differentiating between clinically relevant and irrelevant hemivertebra in small breed brachycephalic dogs.
Subject(s)
Dog Diseases/epidemiology , Dogs/abnormalities , Nervous System Diseases/veterinary , Thoracic Vertebrae/abnormalities , Animals , Cross-Sectional Studies , Dog Diseases/diagnostic imaging , Dog Diseases/genetics , Female , Genetic Predisposition to Disease , Magnetic Resonance Imaging/veterinary , Male , Nervous System Diseases/epidemiology , Nervous System Diseases/etiology , Retrospective Studies , Thoracic Vertebrae/diagnostic imaging , Tomography, X-Ray Computed/veterinaryABSTRACT
The objective of this prospective study was to determine the prevalence of gait abnormalities in a cohort of Swedish pugs by using an owner-based questionnaire targeting signs of gait abnormality and video footage showing the dog's gait. This study also evaluated associated conditions of abnormal gait, including other health disorders prevalent in the breed. Five hundred and fifty (550) pugs registered in the Swedish Kennel Club, of one, five and eight years of age, in 2015 and 2016, were included in the study. Gait abnormalities were reported in 30.7 per cent of the responses. In the majority of cases, the character of the described gait indicated a neurological cause for the gait abnormality. An association was observed between abnormal gait and age, with gait abnormalities being significantly more common in older pugs (P=0.004). An association was also found between abnormal gait and dyspnoea, with dyspnoea being significantly more common in pugs with gait abnormalities (P<0.0001). This study demonstrated that the prevalence of gait abnormalities was high in the Swedish pug breed and increased with age. Future studies on the mechanisms behind these gait abnormalities are warranted.
Subject(s)
Dog Diseases/epidemiology , Lameness, Animal/epidemiology , Animals , Dogs , Female , Male , Prevalence , Prospective Studies , Sweden/epidemiologyABSTRACT
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.
Subject(s)
Dog Diseases/genetics , Genetic Predisposition to Disease , Polyneuropathies/veterinary , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Dogs , Gene Expression Regulation , Intracellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Pedigree , Polyneuropathies/geneticsABSTRACT
BACKGROUND: Hereditary ataxias with similar phenotypes were reported in the Smooth-Haired Fox Terrier, the Jack Russell Terrier and the Parson Russell Terrier. However, segregation analyses showed differing inheritance modes in these breeds. Recently, molecular genetic studies on the Russell group of terriers found independent mutations in KCNJ10 and CAPN1, each associated with a specific clinical subtype of inherited ataxia. The aim of this study was to clarify whether or not Smooth-Haired Fox Terriers with hereditary ataxia and dogs of other related breeds harbor either of the same mutations. A sub goal was to update the results of KCNJ10 genotyping in Russell group terriers. FINDINGS: Three Smooth-Haired Fox Terriers with hereditary ataxia and two Toy Fox Terriers with a similar phenotype were all homozygous for the KCNJ10 mutation. The same mutation was also found in a heterozygous state in clinically unaffected Tenterfield Terriers (n = 5) and, in agreement with previous studies, in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers. CONCLUSIONS: A KCNJ10 mutation, previously associated with an autosomal recessive spinocerebellar ataxia in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers segregates in at least three more breeds descended from British hunting terriers. Ataxic members of two of these breeds, the Smooth-Haired Fox Terrier and the Toy Fox Terrier, were homozygous for the mutation, strengthening the likelihood that this genetic defect is indeed the causative mutation for the disease known as "hereditary ataxia" in Fox Terriers and "spinocerebellar ataxia with myokymia, seizures or both" in the Russell group of terriers.
Subject(s)
Dog Diseases/genetics , Genotype , Mutation , Potassium Channels, Inwardly Rectifying/genetics , Spinocerebellar Degenerations/veterinary , Animals , Dogs , Potassium Channels, Inwardly Rectifying/metabolism , Species Specificity , Spinocerebellar Degenerations/geneticsABSTRACT
Clinical, pathological and genetic examination revealed an as yet uncharacterized juvenile-onset neuroaxonal dystrophy (NAD) in Spanish water dogs. Affected dogs presented with various neurological deficits including gait abnormalities and behavioral deficits. Histopathology demonstrated spheroid formation accentuated in the grey matter of the cerebral hemispheres, the cerebellum, the brain stem and in the sensory pathways of the spinal cord. Iron accumulation was absent. Ultrastructurally spheroids contained predominantly closely packed vesicles with a double-layered membrane, which were characterized as autophagosomes using immunohistochemistry. The family history of the four affected dogs suggested an autosomal recessive inheritance. SNP genotyping showed a single genomic region of extended homozygosity of 4.5 Mb in the four cases on CFA 8. Linkage analysis revealed a maximal parametric LOD score of 2.5 at this region. By whole genome re-sequencing of one affected dog, a perfectly associated, single, non-synonymous coding variant in the canine tectonin beta-propeller repeat-containing protein 2 (TECPR2) gene affecting a highly conserved region was detected (c.4009C>T or p.R1337W). This canine NAD form displays etiologic parallels to an inherited TECPR2 associated type of human hereditary spastic paraparesis (HSP). In contrast to the canine NAD, the spinal cord lesions in most types of human HSP involve the sensory and the motor pathways. Furthermore, the canine NAD form reveals similarities to cases of human NAD defined by widespread spheroid formation without iron accumulation in the basal ganglia. Thus TECPR2 should also be considered as candidate gene for human NAD. Immunohistochemistry and the ultrastructural findings further support the assumption, that TECPR2 regulates autophagosome accumulation in the autophagic pathways. Consequently, this report provides the first genetic characterization of juvenile canine NAD, describes the histopathological features associated with the TECPR2 mutation and provides evidence to emphasize the association between failure of autophagy and neurodegeneration.
Subject(s)
Autophagy/genetics , Dog Diseases/genetics , Dogs/genetics , Mutation, Missense , Nerve Tissue Proteins/genetics , Pantothenate Kinase-Associated Neurodegeneration/veterinary , Amino Acid Motifs , Amino Acid Sequence , Animals , Brain/pathology , Carrier Proteins/genetics , Chromosome Mapping , Conserved Sequence , Dog Diseases/pathology , Dogs/classification , Genes, Recessive , Genetic Association Studies , Humans , Lod Score , Mammals/genetics , Molecular Sequence Data , Nerve Tissue Proteins/physiology , Pantothenate Kinase-Associated Neurodegeneration/genetics , Pantothenate Kinase-Associated Neurodegeneration/pathology , Phenotype , Polymorphism, Single Nucleotide , Sequence Alignment , Sequence Homology, Amino Acid , Spastic Paraplegia, Hereditary/genetics , Species Specificity , Spinal Cord/pathologyABSTRACT
The first cases of early-onset progressive polyneuropathy appeared in the Alaskan Malamute population in Norway in the late 1970s. Affected dogs were of both sexes and were ambulatory paraparetic, progressing to non-ambulatory tetraparesis. On neurologic examination, affected dogs displayed predominantly laryngeal paresis, decreased postural reactions, decreased spinal reflexes and muscle atrophy. The disease was considered eradicated through breeding programmes but recently new cases have occurred in the Nordic countries and the USA. The N-myc downstream-regulated gene (NDRG1) is implicated in neuropathies with comparable symptoms or clinical signs both in humans and in Greyhound dogs. This gene was therefore considered a candidate gene for the polyneuropathy in Alaskan Malamutes. The coding sequence of the NDRG1 gene derived from one healthy and one affected Alaskan Malamute revealed a non-synonymous G>T mutation in exon 4 in the affected dog that causes a Gly98Val amino acid substitution. This substitution was categorized to be "probably damaging" to the protein function by PolyPhen2 (score: 1.000). Subsequently, 102 Alaskan Malamutes from the Nordic countries and the USA known to be either affected (nâ=â22), obligate carriers (nâ=â7) or healthy (nâ=â73) were genotyped for the SNP using TaqMan. All affected dogs had the T/T genotype, the obligate carriers had the G/T genotype and the healthy dogs had the G/G genotype except for 13 who had the G/T genotype. A protein alignment showed that residue 98 is conserved in mammals and also that the entire NDRG1 protein is highly conserved (94.7%) in mammals. We conclude that the G>T substitution is most likely the mutation that causes polyneuropathy in Alaskan Malamutes. Our characterization of a novel candidate causative mutation for polyneuropathy offers a new canine model that can provide further insight into pathobiology and therapy of human polyneuropathy. Furthermore, selection against this mutation can now be used to eliminate the disease in Alaskan Malamutes.
Subject(s)
Cell Cycle Proteins/genetics , Dog Diseases/genetics , Intracellular Signaling Peptides and Proteins/genetics , Polyneuropathies/genetics , Animals , Dogs , Female , Male , MutationABSTRACT
BACKGROUND: An association between the occurrence of calcified discs, visible on radiographic examination (CDVR), and disc extrusions has been suggested in published literature over the past 10-20 years, mainly from Nordic countries. It has also been postulated that dogs without CDVR would not develop disc extrusions. Furthermore, inheritance of CDVR has been calculated and it has been postulated that, by selecting dogs for breeding with few, or no CDVR, the prevalence of disc extrusions in the Dachshund population may be reduced. METHODS: The prevalence of radiographic detectable intervertebral disc calcifications was calculated from one hundred surgeries for disc extrusion, performed in 95 Dachshunds, in order to determine if the disc causing clinically significant IVDD, had radiographic signs of calcification at the time of confirmed disc extrusion. Inclusion criteria, for each dog, included a complete physical, orthopedic and neurologic examination, radiographs of the entire vertebral column, a myelogram or magnetic resonance imaging examination indicating extradural spinal cord compression, and finally a surgical procedure confirming the diagnosis of a disc extrusion. In addition to descriptive statistics, age correlation with number of calcifications visible at radiographic examination and with CDVR at the surgery site was examined. RESULTS: We found that disc extrusions occur as frequently in discs that are found to have radiographic evidence of calcification as those discs that do not have signs of radiographic calcification, and that IVDD (intervertebral disc disease) requiring surgery does occur in the absence of any calcified discs on radiographic examination. We found that calcified discs were more frequent in our Dachshund population compared to previous studies suggesting that disc calcification might be a serious risk factor for developing disc extrusion. Further studies are needed to show, conclusively, if selection of breeding dogs based on CDVR in the Dachshund will reduce the incidence of IVDD. The presence of the calcifications of intervertebral disc should be evaluated with caution, as only part of the calcifications will be detected and the real extent of the disc degeneration may be underestimated.
Subject(s)
Calcification, Physiologic/physiology , Dog Diseases/physiopathology , Intervertebral Disc/physiopathology , Spinal Diseases/veterinary , Age Factors , Animals , Dog Diseases/diagnostic imaging , Dog Diseases/surgery , Dogs , Electromyography/veterinary , Female , Intervertebral Disc/diagnostic imaging , Intervertebral Disc/surgery , Magnetic Resonance Imaging/veterinary , Male , Norway , Radiography , Spinal Diseases/diagnostic imaging , Spinal Diseases/physiopathology , Spinal Diseases/surgeryABSTRACT
PRESENTATION: This report describes a kitten with paraplegia and extensor rigidity of the pelvic limbs associated with motor neuron loss and chronic denervation of skeletal muscle. Persistent skeletal muscle atrophy and degeneration had resulted in immobile stifle and hock joints and severe pelvic limb rigidity consistent with a neurogenic form of arthrogryposis. Both pelvic limbs were equally affected and the kitten showed no signs of pain. INVESTIGATIONS: Electromyography identified spontaneous activity in the pelvic limbs. Muscle and peripheral nerve biopsies showed pathology consistent with denervation. On necropsy, 3 weeks after admittance, severe degenerative changes including axonal necrosis and myelin degeneration were confirmed in the lumbar spinal cord. CLINICAL RELEVANCE: There are very few descriptions of feline motor neuron degeneration in the literature and obtaining an ante-mortem diagnosis is difficult. Although an inherited disorder cannot be ruled out, a condition acquired congenitally in utero or postnatally was suspected in this case.