Leukocyte and cytokine variables in asymptomatic Pugs at genetic risk of necrotizing meningoencephalitis

Windsor, Rebecca; Stewart, Samuel D.; Talboom, Joshua S.; Lewis, Candace R.; Naymik, Marcus; Piras, Ignazio S.; Keller, Simone; Borjesson, Dori L.; Clark, Gary M.; Khanna, Chand; Huentelman, Matthew J.

doi:10.1111/jvim.16293

Cited by 4 publications

(13 citation statements)

References 19 publications

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“…17 After conducting haplotype association analysis in Haploview, we found 5 haplotypes within this LD block in the Barber et al cohort: 1 associated with increased NME risk (88.6% frequency in cases, 27.1% frequency in controls; P = 1.3EÀ13), and the remaining haplotypes were associated with decreased NME risk. 13,16,17 To assess NME risk in this study cohort, we extracted the same 7 SNPs from the Illumina Canine HD BeadChip data and haplotypes were phased using the default options in Beagle 5.2. 21 Dogs in the cohort are defined as having low genomic risk (no genomic risk allele identified) and at genomic risk (presence of 1 or 2 risk alleles).…”

Section: Nme Risk Genotype Assessmentmentioning

confidence: 87%

“…We identified an LD block of 146 kb encompassing 7 SNPs including the top pug NME GWAS SNP, BICF2P194998 17 . After conducting haplotype association analysis in Haploview , we found 5 haplotypes within this LD block in the Barber et al cohort: 1 associated with increased NME risk (88.6% frequency in cases, 27.1% frequency in controls; P = 1.3E−13), and the remaining haplotypes were associated with decreased NME risk 13,16,17 . To assess NME risk in this study cohort, we extracted the same 7 SNPs from the Illumina Canine HD BeadChip data and haplotypes were phased using the default options in Beagle 5.2 21 .…”

Section: Methodsmentioning

confidence: 99%

“…13,16,17 There are systemic inflammatory changes in asymptomatic but genetically at-risk pugs. 17 This led to the hypothesis that young asymptomatic genetically at-risk pugs might have subclinical brain inflammation associated with the systemic inflammatory signature. Furthermore, we hypothesized that these young genetically at-risk pugs might have subtle abnormalities on neurological examination that precede the conventionally recognized clinical signs typically associated with NME.…”

Section: Introductionmentioning

confidence: 99%

“… 15 MHC II gene mutations are also associated with increased risk for multiple sclerosis (MS) in humans, and NME in pugs mimics the clinical, imaging, and pathological characteristics of the acute fulminant or nonprototypic forms of MS. 16 The incidence of NME in pugs is approximately 1% to 2%, whereas the incidence of the high‐risk haplotype in a homozygous state has a reported range of 6% to 18%, suggesting a multifactorial disease. 13 , 16 , 17 …”

Section: Introductionmentioning

confidence: 99%

“…There are systemic inflammatory changes in asymptomatic but genetically at‐risk pugs 17 . This led to the hypothesis that young asymptomatic genetically at‐risk pugs might have subclinical brain inflammation associated with the systemic inflammatory signature.…”

Section: Introductionmentioning

confidence: 99%

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A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at‐risk pug dogs

Windsor¹,

Stewart²,

Schmidt³

et al. 2022

Veterinary Internal Medicne

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Background: Necrotizing meningoencephalitis (NME) in the pug dogs is a fatal neuroinflammatory disease associated with rapid progression and poor response to conventional immunosuppressive therapy. Diagnosis is typically made after severe neurological abnormalities have manifested.Hypothesis/Objective: Pug dogs at genetic risk for NME might manifest neurological abnormalities before developing pathognomonic clinical signs of NME.Animals: Thirty-six pug dogs less than 4 years of age asymptomatic for NME.Methods: Prospective observational cohort study with germline genome-wide genotyping. Neurological examinations were performed 4 weeks apart to document reproducible findings of central nervous system disease. Magnetic resonance imaging, cerebrospinal fluid analysis, and testing for infectious diseases were performed in all pugs with reproducible abnormalities detected on neurological examination. Results:The overall risk allele frequency in this cohort was 40%; 5 (14%) dogs were high risk, 19 (53%) dogs were medium risk, and 12 (33%) dogs were low genetic risk for NME. Reproducible abnormalities detected on neurological examination were identified in 8/24 (33%) genetically at-risk dogs and 0/12 (0%) low risk dogs.Clinical abnormalities included multifocal spinal pain in 8/8, reduced menace response in 5/8, and lateralizing postural reaction deficits in 5/8 pugs. There was a strong association between genotype risk and the presence of this clinical phenotype (P = .03).Conclusions and Clinical Importance: Our findings suggest the presence of a novel early clinical phenotype of NME in apparently asymptomatic genetically at-risk pugs which might be used to plan early diagnostic and therapeutic clinical trials.

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Section: Nme Risk Genotype Assessmentmentioning

confidence: 87%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at‐risk pug dogs

Windsor¹,

Stewart²,

Schmidt³

et al. 2022

Veterinary Internal Medicne

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Assessment of glial fibrillary acidic protein and anti‐glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy

Rohdin,

Ljungvall,

Jäderlund

et al. 2024

Veterinary Record

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BackgroundPugs 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.MethodsThe 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.ResultsThis 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).LimitationsThe 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.ConclusionsThe 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.

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Vertebral and spinal malformations in small brachycephalic dog breeds: Current knowledge and remaining questions

De Decker,

Rohdin,

Gutierrez-Quintana

2024

The Veterinary Journal

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Leukocyte and cytokine variables in asymptomatic Pugs at genetic risk of necrotizing meningoencephalitis

Cited by 4 publications

References 19 publications

A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at‐risk pug dogs

A potential early clinical phenotype of necrotizing meningoencephalitis in genetically at‐risk pug dogs

Assessment of glial fibrillary acidic protein and anti‐glial fibrillary acidic protein autoantibody concentrations and necrotising meningoencephalitis risk genotype in dogs with pug dog myelopathy

Vertebral and spinal malformations in small brachycephalic dog breeds: Current knowledge and remaining questions

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