Studies look for potential therapy targets for dogs with Chiari-like malformation

A pair of studies from North Carolina State University looked for biomarkers and genetic markers of a syndrome associated with skull malformations common in Cavalier King Charles spaniels (CKCS) and other toy breeds. The findings could lead to better targeted therapeutics for symptoms as well as potential genetic targets for treatment.

Chiari-like malformation (CM) is a congenital disease characterized by a mismatch in size between the cranial vault of the skull that protects the brain and its contents. The disease is also associated with syringomyelia (SM), a condition where a fluid-filled cavity forms within the spinal cord.

Cavalier King Charles spaniels have a high prevalence of CM and SM, and both conditions can cause neuropathic pain and phantom itching, where the dog scratches at the head and neck without making contact.

“Understanding the source of the clinical signs of CM and SM is complicated given the signs and MRI findings don’t always match,” says Natasha Olby, Dr. Kady M. Gjessing and Rahna M. Davidson Distinguished Chair in Gerontology at NC State. Olby is the corresponding author of both studies.

“We know that humans with neuropathic pain and migraine have elevated levels of a biomarker called Calcitonin Gene-Related Peptide (CGRP), and antagonists to CGRP signaling have provided some effective migraine treatments,” Olby says. “But no one has ever measured the levels of this biomarker in Cavalier King Charles spaniels.”

In the first study, Olby and her team looked at 29 CKCS – using imaging, cerebrospinal fluid samples and pain evaluation – and found that levels of CGRP were elevated in dogs with CM and with painful symptoms, but that CGRP levels were not correlated with the presence of SM.

“In people, SM causes pain, abnormal sensations and weakness in extremities, but in dogs, even when we see the condition there may not necessarily be clinical signs,” Olby says. “Although this was a small study, it points to CGRP as an active pathway in CM, which presents a potential avenue for future therapy.”

In the second study, the team looked for genetic markers associated with the presence of clinical signs of CM and SM.

“The discomfort associated with CMSM is distressing,” Olby says. “Finding genetic markers for the disease would not only give us better insight into the disease itself and treatment pathways, it could also allow CKCS breeders to breed away from the trait entirely.”

The researchers took DNA samples and did MRI imaging on 179 CKCS. Owners also filled out questionnaires regarding their dog’s symptoms and behavior.

The findings were mixed.While no specific regions were associated with the presence of SM alone, the presence of signs of pain and scratch was associated with a region on one chromosome that had previously been associated with skull changes in these dogs.

“We identified a region of interest in a gene also identified by another group using different methods,” Olby says. “This work confirms the area as a region of interest and gives us a place to focus our future work.”

The papers, “Cerebrospinal Fluid Concentrations of Calcitonin Gene Related Peptide in Dogs with Chiari-like Malformation” and “Cerebrospinal Fluid Concentrations of Calcitonin Gene Related Peptide in Dogs with Chiari-like Malformation” appear in the Journal of Veterinary Internal Medicine and BMC Veterinary Research, respectively. Co-authors from NC State are John D. Macri, Courtney Sparks, Zachary Anderson, Michael W Vandewege and Meghan Leber. Jonah N. Cullen and Steven G. Friedenberg of the University of St. Paul co-authored the BMC Veterinary Research paper. The work was supported by the Cavalier King Charles Spaniel USA Health Foundation, the American Cavalier King Charles Spaniel Club Charitable Trust (through the American Kennel Club Canine Health Foundation grant number 02162-MOU), and the National Institutes of Health (grant number F30OD025357).

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Note to editors: Abstracts follow.

“Cerebrospinal Fluid Concentrations of Calcitonin Gene Related Peptide in Dogs with Chiari-like Malformation”

DOI: 10.1111/jvim.70105

Authors: John D. Macri, Courtney Sparks, Zachary Anderson, Natasha Olby, North Carolina State University
Published: May 3, 2025 in the Journal of Veterinary Internal Medicine

Abstract:
Background
The biomarker Calcitonin Gene-Related Peptide (CGRP) is elevated in human conditions associated with neuropathic pain, but has not yet been studied in Cavalier King Charles Spaniels (CKCS) with Chiari-like malformation (CM).
Hypothesis/Objectives
Cavalier King Charles Spaniels with clinical signs of CMSM would have higher CSF concentrations of CGRP than asymptomatic CKCS. Our aim was to measure CSF CGRP concentrations in CKCS with and without clinical signs of CMSM.
Animals
Twenty-nine CKCS drawn from research and clinical cases underwent quantification of pain and scratching, a brain and spinal cord MRI, and lumbar CSF collection.
Methods
This was a prospective study with both normal and clinically affected CKCS recruited. The CSF concentration of CGRP (C-CGRP) was measured using an ELISA assay. Dogs were grouped by the presence of SM, pain, and scratching, and concentrations of C-CGRP were compared between groups using Wilcoxon Rank Sum. The concentration of C-CGRP, pain score, and SM diameter were evaluated using linear regression.
Results
Concentration of C-CGRP was significantly higher in painful dogs (median 116.1, range: 11.6–238.3 pg/mL) as compared to non-painful dogs (median 77.7 pg/mL, range 0–266.2 pg/mL; p = 0.0124). No significant difference in C-CGRP concentration was noted between dogs with (median 99.3, range 0–226.6 pg/mL) and without (median 102.2, range 6.0–266.2 pg/mL) SM (p = 0.305).
Conclusions and Clinical Importance
Cerebrospinal fluid CGRP concentration is elevated in CKCS exhibiting pain regardless of the presence of SM. CGRP might contribute to neuropathic pain in CMSM and could be a target for therapeutic intervention.

“Genomic analyses in Cavalier King Charles spaniels identify loci associated with clinical signs of Chiari-like malformation and Syringomyelia”

DOI: 10.1186/s12917-025-04754-4

Authors: Courtney R. Sparks, Michael W. Vandewege, Meghan Leber & Natasha J. Olby, North Carolina State University; Courtney R. Sparks, Michael W. Vandewege, Meghan Leber, University of Minnesota
Published: May 3, 2025 in BMC Veterinary Research

Abstract:
Background
Chiari-like malformations (CM) and syringomyelia (SM) are common in Cavalier King Charles spaniels (CKCS) leading to variable manifestations of pain and scratch. Inheritance studies suggest a polygenic mode of inheritance and association studies have identified loci associated with the presence of SM on MRI. Given the poor correlation of clinical signs of CMSM with MRI findings, we hypothesized that an association study with clinical signs as the phenotype could reveal new loci of interest. The objectives of this study were to perform genome-wide association studies on CKCS using SM and clinical sign phenotypes of pain and scratch and to use whole genome sequencing (WGS) to identify variants in regions of interest. We collected DNA on 174 CKCS. Owners completed questionnaires to establish the clinical pain and scratch phenotype and magnetic resonance imaging (MRI) was used to identify CM and SM (linear T2 hyperintensity greater than 2 mm in height) in all dogs. Dogs were genotyped using the Axiom K9 HD (710,000 snps) array. GWAS analyses were performed using GEMMA and categorical and quantitative approaches were used to define clinical phenotypes. Whole genome sequencing (WGS) was performed on an Illumina HiSeq 4000 high-throughput sequencing system.
Results
There were no regions associated with SM presence. The presence of signs of pain and scratch was associated with a region on Canis familiaris autosome (CFA) 26 downstream of ZWINT, previously associated with skull changes in CKCS with SM, although genome-wide significance was not reached. Loci were also associated with quantitative pain and scratch scores on CFA 13, 2 and 38. There were 66 variants that segregated with phenotype including 2 missense variants that were predicted to have moderate effects on ZWINT function.
Conclusions
The identification of a locus on CFA26 using the clinical phenotype of pain and scratch that coincided with a locus identified in a morphological study provides strong support for this as a region of interest.