Inheritance of Chiari-Like Malformation: Can a Mixed Breeding Reduce the Risk of Syringomyelia?

<div><p>Canine Chiari-like malformation (CM) is a complex abnormality of the skull and craniocervical junction associated with miniaturization and brachycephaly which can result in the spinal cord disease syringomyelia (SM). This study investigated the inheritance of CM in a Griffon Bruxellois (GB) family and feasibility of crossbreeding a brachycephalic CM affected GB with a mesaticephalic normal Australian terrier and then backcrossing to produce individuals free of the malformation and regain GB breed characteristics. The study family cohort (n = 27) included five founder dogs from a previous baseline study of 155 GB which defined CM as a global malformation of the cranium and craniocervical junction with a shortened skull base and increased proximity of the cervical vertebrae to the skull. T1-weighted sagittal DICOM images of the brain and craniocervical junction were analysed for five significant traits (two angles, three lines) identified from the previous study and subsequent Qualitative Trait Loci analysis. Mean measurements for mixed breed, pure-breed and baseline study groups were compared. Results indicated that mixed breed traits posed less risk for CM and SM and were useful to distinguish the phenotype. Moreover on the MR images, the filial relationships displayed by the traits exhibited segregation and those presenting the greatest risk for CM appeared additive towards the severity of the condition. The external phenotypes revealed 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. The four GB affected with SM in the study all exhibited reduced caudal skull development compared to their relatives. The craniocervical traits may be useful for quantifying CM and assessing the possibility of SM thus assisting breeders with mate selection. However, such a system requires validation to ensure appropriateness for all breeds at risk.</p></div

Explanation of the calculation of values.

<p>Abbreviations: CCF = caudal cranial fossa. Symbols in equations: a = parenchyma within the cranial cranial fossa, b = cerebellum, c = brainstem, d = CCF, e = cerebellum within the caudal part of the CCF, f = cerebellum within the rostral part of the CCF, g = caudal part of the CCF, h = rostral part of the CCF.</p

Masks recorded from MR images.

<p>Masks were recorded for the following volumes (mid-saggital view): Parenchyma within the cranial cranial fossa (red), cerebellum (purple), brainstem (dark green), CCF (light green). A mask for the cranial cranial fossa was not recorded but is shown here for completeness (blue).</p

Cerebellar crowding within different parts of the caudal cranial fossa comparing Labradors, small breed dogs and Cavalier King Charles Spaniels.

<p>Crowding of cerebellum is defined as the percentage of the volume of each part of the caudal cranial fossa (CCF) which is occupied by cerebellar parenchyma (panel A: Rostral Cerebellar CCF Percentage, panel B: Caudal Cerebellar CCF Percentage). Cavalier King Charles Spaniels (CKCS) have a more crowded rostral CCF than Labradors and more crowded caudal CCF than small breed dogs or Labradors. *p<0.05, ***p<0.001.</p

Relationship between Cerebellar Crowding and Cerebellar Volume.

<p>Crowding of cerebellum is defined as the percentage of the volume of each part of the caudal cranial fossa (CCF) which is occupied by cerebellar parenchyma (panel A: Rostral Cerebellar CCF Percentage, panel B: Caudal Cerebellar CCF Percentage). The volume of the cerebellum is expressed as a percentage of the total brain volume (Cerebellar Brain Percentage). Fitted linear regression lines are also displayed. Cavalier King Charles Spaniels (CKCS) showed a relationship between cerebellar crowding and volume in both the rostral CCF (p = 0.0008) and caudal CCF (p = 0.0003) and Labradors (LD) and small breed dogs (SB) did not. In CKCS the slope of the fitted model in the caudal CCF was significantly steeper than in the rostral CCF (p = 0.03668), indicating that crowding in the caudal CCF is more sensitive to changes in cerebellar volume.</p

Cerebellar crowding within different parts of the caudal cranial fossa comparing different groups of Cavalier King Charles Spaniels.

<p>Crowding of cerebellum is defined as the percentage of the volume of each part of the caudal cranial fossa (CCF) which is occupied by cerebellar parenchyma (Rostral Cerebellar CCF Percentage and Caudal Cerebellar CCF Percentage). CKCS under 2 years of age with Chiari-like malformation (CM) and syringomyelia (SM) (CKCS CM/SM) have a more crowded Rostral CCF and Caudal CCF than CKCS over 5 years of age with CM but without SM (CKCS CM). *p<0.05.</p

Morphometric measurements for three generation the F2 backcross pedigree.

<p>Morphometric measurements for three generation the F2 backcross pedigree.</p

Head conformation and associated angle FAC in six relatives of Bitch H with and without SM.

<p>TW1 sagittal MRI of the caudal fossa and cranial-cervical junctions with superimposed morphometric framework of lines and angles for parents and offspring enhances comparison. The differences in the size of angle FAC are reflected in the lack of skull development caudal to the ear pinna (behind the ears) for dogs with SM compared to dogs with no SM (‘normal’ caudal skull shaded aqua colour). The photos of the heads have been resized to allow comparison using two vertical lines (black) placed at the outer eye and the origin of the external pinna (red) a consistent distance apart.</p

Cerebellar volume.

<p>The volume of the cerebellum is expressed as a percentage of the caudal cranial fossa volume (Panels A and B: Cerebellar CCF Percentage) and a percentage of the total brain volume (Panels C and D: Cerebellar Brain Percentage). Cavalier King Charles Spaniels (CKCS) have a relatively larger cerebellum than small breed dogs and Labradors (Panels A and C). CKCS under 2 years of age with Chiari-like malformation (CM) and syringomyelia (SM) (CKCS CM/SM) have a relatively larger cerebellum than CKCS over 5 years of age with CM but without SM (CKCS CM, Panels B and D). *p<0.05, **p<0.01, ***p<0.001.</p

Descriptive Statistics for five traits in Mixed, Pure and control GB Groups.

<p>Descriptive Statistics for five traits in Mixed, Pure and control GB Groups.</p