Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s) (MIM number): 118420 (trait)

Links to MONDO diseases: No links.

Mendelian trait/disorder: no

Mode of inheritance: Multifactorial

Considered a defect: yes

Key variant known: no

Species-specific name: The disease is also called Arnold Chiari malformation; caudal occipital malformation syndrome; occipital hypoplasia; hindbrain herniation; Chiari-like malformation

Species-specific symbol: CM

Mapping: From a GWAS conducted on 50 affected and 24 non-affected Griffon Bruxellois Dogs, each genotyped with the Illumina CanineHD Beadchip (yielding 74,399 informative SNPs), Lemay et al. (2014) identified putative QTL on each of five chromosomes, namely CFA2, CFA9, CFA12, CFA14 and CFA24. The authors noted that the CFA2 QTL includes a comparative functional candidate gene, namely Sall-1, mutations in which give rise to a somewhat similar disorder in humans (Townes-Brocks syndrome). Andrino et al. (2022): "A genome-wide association study (GWAS) was carried out comparing the whole genome sequences (WGS) from 12 dogs with SHM [syringohydromyelia] and 2 panels of 26 dogs (either older than 5 years and showing the absence of SHM or belonging to breeds not susceptible to SHM) to identify candidate genes associated with the development of SHM. Seven candidate genes were identified. Of these, five genes were determined to be involved in bone development (PLXNA2, HHAT, MBOAT2, ITGAV) and calcium homeostasis (HPCAL1). Although further validation is needed at the transcript level, it is worth highlighting the association of a possible pathogenic variant which generated a new intronic branch-site sequence in PLXNA2 (T/C, CFA7:7043294)."

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Neurological exams may reveal neuropathic pain, weakness and proprioceptive deficits. Reported signs of neuropathic pain include vocalisation, reduced activity, touch aversion and sleep disturbance (Rusbridge, 2020). This is often seen in dogs with more extreme brachycephaly. Common syringomyelia-specific signs include “phantom scratching, scoliosis and sensory and motor signs” (Rusbridge, 2020). Localisation of the neurological signs are consistent with the syrinx location. However, these are only observed in dogs with large syrinxes ≥ 4mm in transverse width. The signs can be intermittent and are often exacerbated during periods of excitement, stress or tactile stimulus like contact by a neck collar (Hechler and Moore, 2018). [IT thanks DVM student Grace Zheng, who provided the basis of this contribution in April 2022.]

Pathology: Development of fluid-filled cavitations of the spinal cord (syrinxes) is characteristic (Rusbridge, 2020). Fluid signal-void signs may also be detected by MRI within the syrinx cavity. This is indicative of an active and filling syrinx with turbulent flow. However, not all syrinxes are clinically significant. A quiescent syrinx is symmetrical with little change to the outline of the spinal cord, while a pathological syrinx generally has an asymmetrical appearance. Other features associated with the disease detected by MRI include conformational changes such as “increased cranial height, rostral displacement of atlas and dens, overcrowding of craniocervical junction and obstruction of CSF flow through the foramen magnum” (Rusbridge, 2020). [IT thanks DVM student Grace Zheng, who provided the basis of this contribution in April 2022.]

Control: Knowler et al (2016) investigated the "feasibility of crossbreeding a brachycephalic CM affected GB [Griffon Bruxellois] with a mesaticephalic normal Australian terrier and then backcrossing to produce individuals free of the malformation and regain GB breed characteristics" and concluded "that by outcrossing breed types and with careful selection of appropriate conformation characteristics in the first generation, it is possible to regain the GB breed standard and reduce the degree of CM".

Breeds: Affenpinscher (Dog) (VBO_0200003), Brussels Griffon (Dog) (VBO_0200241), Cavalier King Charles Spaniel (Dog) (VBO_0200309), Chihuahua (Dog) (VBO_0200338), King Charles Spaniel (Dog) (VBO_0200765).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below