Chiari malformation type I: what information from the genetics?

PURPOSE: Chiari malformation type I (CMI), a rare disorder of the craniocerebral junction with an estimated incidence of 1 in 1280, is characterized by the downward herniation of the cerebellar tonsils of at least 5 mm through the foramen magnum, resulting in significant neurologic morbidity. Classical CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior cranial fossa which is too small to accommodate the normal-sized cerebellum. In this review, we dissect the lines of evidence supporting a genetic contribution for this disorder. METHODS: We present the results of two types of approaches: animal models and human studies encompassing different study designs such as whole genome linkage analysis, case-control association studies, and expression studies. The update of the literature also includes the most recent findings emerged by whole exome sequencing strategy. RESULTS: Despite evidence for a genetic component, no major genes have been identified and the genetics of CMI is still very much unknown. One major challenge is the variability of clinical presentation within CMI patient population that reflects an underlying genetic heterogeneity. CONCLUSIONS: The identification of the genes that contribute to the etiology of CMI will provide an important step to the understanding of the underlying pathology. The finding of a predisposing gene may lead to the development of simple and accurate diagnostic tests for better prognosis, counseling, and clinical management of patients and their relatives.

Diffusion Tensor Imaging in Syringomyelia Secondary to Chiari Malformation in Cavalier King Charles Spaniel-A Preliminary Study.

Syringomyelia secondary to Chiari-like malformation (so-called CM-SM syndrome) is a common disorder in Cavalier King Charles Spaniels (CKCS) that is diagnosed using standard structural MRI, though imaging findings often do not correlate with the severity of clinical symptoms. Diffusion tensor imaging (DTI) is a technique that defines subtle microstructural changes in the course of many brain and spinal cord diseases, that are not visible on standard MRI. The aim of the study was to identify the correlation between the presence of clinical symptoms and DTI parameters, such as apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within the spinal cord in the course of CM-SM. Study subjects included 18 dogs, CKCS with MRI-confirmed SM (SM group), and 12 CKCS dogs without SM (non-SM group). The SM group was divided into SM-symptomatic group (n = 8) and SM-asymptomatic group, n = 10). All dogs underwent same clinical and neurological assessment followed by MRI examination. All MRI studies were performed on a 1.5T MRI scanner. The MRI spine protocol included: transverse and sagittal T2-weighted images followed by DTI performed in the sagittal plane. The measurements of FA and ADC values were performed manually using the region of interest (ROI) method at the level of three intervertebral discs between C1 and C4. Notable differences in age and body weight were found. No significant differences in FA and ADC values between the SM and non-SM groups were found, but between non-SM, SM-asymptomatic and SM-symptomatic groups significant differences were found in ADC values in all three ROIs and in FA values in ROI-1 and ROI-3. SM-symptomatic dogs compared to non-SM, showed decreased FA value in ROI-1 and ROI-3 also increased ADC value in ROI-1, ROI-2 and ROI-3. SM-symptomatic dogs compared to SM-asymptomatic showed also decreased FA value in ROI-1 and ROI-3, and also increased ADC value in ROI-1, ROI-2 and ROI-3. The results suggest that the values of DTI parameters correlate with the severity of clinical symptoms in the course of CM-SM in animals. The use of DTI evaluation of CM-SM patients carries a potential value as a clinically relevant protocol for an objective assessment of the spinal cord.