A groundbreaking pair of studies emerging from North Carolina State University is shedding new light on Chiari-like malformation (CM) and syringomyelia (SM)—two debilitating neurological conditions afflicting Cavalier King Charles spaniels (CKCS) and other toy breeds. These canine syndromes, characterized by skull malformations and fluid-filled cavities within the spinal cord, have long baffled veterinary neurologists due to the complex interplay between anatomical abnormalities and clinical symptoms. Now, with targeted biomarker analysis and genomic explorations, researchers are identifying critical molecular and genetic elements that pave the way for innovations in diagnosis, therapy, and potentially, breeding strategies.
Chiari-like malformation represents an inherited congenital defect marked by a size discrepancy between the braincase and its cranial contents. This anatomical mismatch leads to crowding at the base of the skull and is frequently linked to syringomyelia, a progressive spinal cord disorder wherein fluid-filled syrinxes develop, causing neuropathic pain and sensory abnormalities. In CKCS, these conditions manifest in vexing clinical signs, including severe head and neck pain and a peculiar, phantom itching that compels dogs to scratch at nonexistent irritants, complicating assessment and treatment protocols.
The neurological complexity is accentuated by a disconnection between imaging findings and clinical presentations. Magnetic resonance imaging (MRI), while invaluable, often reveals a poor correlation between the visible severity of malformations and the dog’s exhibited symptoms. As Dr. Natasha Olby, distinguished chair in gerontology at North Carolina State and lead investigator, points out, grasping the underlying pathophysiology requires transcending traditional imaging to explore molecular pathways governing neuropathic pain and neural dysfunction in CMSM.
Taking a novel approach, Olby and her colleagues focused on Calcitonin Gene-Related Peptide (CGRP), a neuropeptide renowned for its prominent role in human neuropathic pain syndromes such as migraine. Elevated levels of CGRP in cerebrospinal fluid (CSF) and the efficacy of CGRP antagonists in human patients hinted at a similar pathophysiological mechanism in CM-affected dogs, yet this marker had never been investigated in the canine population. The team hypothesized that CGRP concentrations in the CSF might parallel the severity of clinical signs in CKCS with CM and SM.
In their first study, the researchers meticulously examined 29 CKCS dogs spanning both clinically affected and asymptomatic cohorts. Employing advanced imaging, lumbar CSF collection, and stringent pain and scratching assessments, the study unveiled that CSF concentrations of CGRP were significantly elevated in dogs displaying pain symptoms indicative of neuropathic distress. Intriguingly, CGRP levels did not correlate with the mere presence of syringomyelia as detected by MRI, emphasizing that neuropathic pain and anatomical abnormalities might be mediated through distinct neurochemical pathways.
This revelation carries profound clinical implications. While syringomyelia is indeed a hallmark of CM progression, its presence alone cannot reliably predict neuropathic pain, complicating therapeutic decisions. The study’s demonstration of elevated CGRP in symptomatic dogs opens an avenue for exploring CGRP antagonists—already revolutionizing headache medicine in humans—as a promising new therapeutic strategy for dogs suffering from CMSM-related neuropathic pain. Such treatments could profoundly improve quality of life, offering targeted relief where prior analgesic options often fell short.
Complementing the biomarker investigation, the second study delved into the genetic architecture underlying CMSM symptomatology in a large cohort of 179 CKCS. Given the syndrome’s complex inheritance pattern and the disappointing lack of clear genotype-phenotype correlations historically, this work sought to identify genomic loci associated specifically with clinical symptoms—namely pain and scratching—rather than relying solely on imaging phenotypes such as the presence of syringomyelia.
Utilizing state-of-the-art genome-wide association studies (GWAS) and whole-genome sequencing (WGS), the researchers genotyped the dogs using the high-density Axiom K9 HD array, interrogating over 700,000 single nucleotide polymorphisms (SNPs). Clinical phenotyping was rigorously obtained through owner-reported questionnaires detailing the manifestation of pain and scratch behaviors. This integrative approach leverages both detailed clinical data and high-resolution genetic analysis to dissect the complex polygenic basis of CMSM.
While the study found no genetic regions significantly associated with the mere radiographic presence of syringomyelia, it identified a compelling locus on canine chromosome 26 (CFA26) correlated with clinical pain and scratch symptoms. This genomic region aligns downstream of the gene ZWINT, previously implicated in cranial morphological anomalies in CKCS with syringomyelia. Additional loci on chromosomes 2, 13, and 38 were linked to quantitative measures of pain and scratching intensity, broadening the understanding of the polygenic landscape influencing these neurological symptoms.
Notably, within the CFA26 locus, the team pinpointed 66 genetic variants segregating with clinical phenotypes, including two missense mutations predicted to moderately affect ZWINT function. ZWINT encodes a kinetochore-associated protein critical to cell cycle regulation, implying that altered cellular mechanisms might contribute to skull development abnormalities and subsequent neural complications. These genetic discoveries provide a molecular foothold for future targeted research and breed-based interventions aimed at reducing disease prevalence.
Together, these studies underscore a pivotal shift in CMSM research, moving beyond purely anatomical observations to integrate molecular neurobiology and genetics. By associating elevated CGRP with neuropathic pain and uncovering specific genetic markers linked to clinical symptomatology, the work lays a foundation for multi-dimensional diagnostic tools and therapeutic targets. Such advancements hold significant promise not only for affected CKCS but also for broader applications in veterinary neurology and comparative medicine.
Furthermore, these data equip breeders with actionable insights, potentially enabling selective breeding programs designed to diminish the incidence of CMSM by avoiding transmission of high-risk genetic variants. Taken together, this represents a harmonious blend of clinical neuroscience, veterinary genetics, and translational therapeutics that could dramatically enhance the wellbeing of vulnerable toy breed populations.
Beyond the immediate implications for canine health, the parallels between CMSM in CKCS and human Chiari malformation and syringomyeliaa highlight the value of this research within a One Health context. Insights into CGRP pathways and genetic susceptibilities in dogs may inform human neurology, advancing understanding across species boundaries and accelerating drug development for neuropathic pain syndromes.
This investigative effort was made possible by collaborative input from experts at North Carolina State University and the University of St. Paul, funded by prestigious organizations including the Cavalier King Charles Spaniel USA Health Foundation, the American Cavalier King Charles Spaniel Club Charitable Trust, and the U.S. National Institutes of Health. The resulting publications in the Journal of Veterinary Internal Medicine and BMC Veterinary Research on May 3, 2025, have set a new standard, igniting hope for transformative progress in diagnosing and treating Chiari-like malformation and syringomyelia in dogs.
The journey from complex neuroanatomical malformations to the identification of CGRP as a biomarker—and finally to illuminating key genetic loci—epitomizes the power of integrated biomedical research. As veterinary and human medicine converge on shared molecular targets, the coming years promise innovative therapies, refined clinical criteria, and a brighter future for pets suffering from these neurologically devastating conditions.
Subject of Research: Animals (Cavalier King Charles spaniels)
Article Title: “Cerebrospinal Fluid Concentrations of Calcitonin Gene Related Peptide in Dogs with Chiari-like Malformation”
News Publication Date: May 3, 2025
Web References:
- https://onlinelibrary.wiley.com/doi/10.1111/jvim.70105
- https://bmcvetres.biomedcentral.com/articles/10.1186/s12917-025-04754-4
References: Macri JD et al., Journal of Veterinary Internal Medicine, 2025; Sparks CR et al., BMC Veterinary Research, 2025.
Image Credits: North Carolina State University
