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

Abstract

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.

Allele frequency of a genetic risk variant for necrotizing meningoencephalitis in pug dogs from Europe and association with the clinical phenotype

“…The present investigation demonstrated an allele frequency of the risk variant of 25.7% in the European study population. These results are similar to a recent North American investigation ( 37 ). The results demonstrated also that dogs with a clinical NME phenotype were significantly more likely homozygous for the NME risk variant on CFA12 than dogs ≥6 years without neurological signs ( p = 0.008) thus providing further support for the pathogenic potential of the variant or the associated haplotype.…”

“…This study described the genetic test results of 6,135 European pugs tested for the CFA12:2605517delC variant on the DLA-DPB1 gene. The results demonstrated a surprisingly high allele frequency of the gene variant in the European pug population (25.7%), with 7.4% of the European pugs at high risk and 13.8% of the questionnaire cohort at high risk, as defined previously ( 37 ), but stays in contrast to other studies ( 38 ). Questionnaire data on the neurological signs and disease course of a representative subgroup indicate that the genetic risk variant is associated with an NME phenotype.…”

“…In this study, 19 dogs with a homozygous NME/NME genetic test result did not show neurological signs or seizures; however, 10 of them were still younger than 6 years at the time of the questionnaire. It is possible that these pugs could still develop an NME, or had only a subclinical phenotype of NME as proposed by others ( 37 ). The further clinical course of these dogs was unknown.…”

“…The association between the MHC class II proteins and disease development is also known in humans with multiple sclerosis (MS) ( 28 ). A recent study described a potential early clinical phenotype of NME in asymptomatic but genetically at risk pugs, which might suggest the need to start early diagnosis and therapy for these dogs even in the absence of neurological signs ( 37 , 41 ).…”

“…None of the dogs with suspected IE was at risk for NME (homozygous), but five out of six dogs showed a low risk for NME (heterozygous). As the MRIs were unavailable for review, we cannot exclude subtle MRI changes in heterozygous dogs as proposed in a recent study ( 37 ).…”