Chiari type 1 deformity pathogenesis
Cranial bone constriction is suspected to be the most common biologic mechanism leading to Chiari type 1 deformity. However, other mechanisms may also contribute, particularly in the presence of connective tissue diseases (CTDs), such as Ehlers-Danlos Syndrome (EDS).
Genetics
Accumulating data suggest CM-1 with connective tissue diseases (CTD+) may have a different patho-mechanism and different genetics than CM-1 without CTDs (CTD-). To identify CM-1 genetic risk variants, Urbizu et al. performed whole exome sequencing on a single large, multiplex family from Spain and targeted sequencing on a cohort of 186 unrelated adult, Caucasian females with CM-1. Targeted sequencing captured the coding regions of 21 CM-1 and EDS candidate genes, including two genes identified in the Spanish family. Using genetic burden analysis, they compared the frequency of rare, functional variants detected in CM-1 cases versus publically available ethnically-matched controls from gnomAD. A secondary analysis compared the presence of rare variants in these genes between CTD+ and CTD- CM-1 cases. In the Spanish family, rare variants co-segregated with CM-1 in COL6A5, ADGRB3 and DST. A variant in COL7A1 was present in affected and unaffected family members. In the targeted sequencing analysis, rare variants in six genes (COL7A1, COL5A2, COL6A5, COL1A2, VEGFB, FLT1) were significantly more frequent in CM-1 cases compared to public controls. In total, 47% of CM-1 cases presented with rare variants in at least one of the four significant collagen genes and 10% of cases harbored variants in multiple significant collagen genes. Moreover, 26% of CM-1 cases presented with rare variants in the COL6A5 gene. We also identified two genes (COL7A1, COL3A1) for which the burden of rare variants differed significantly between CTD+ and CTD- CM-1 cases. A higher percentage of CTD+ patients had variants in COL7A1 compared to CTD+ patients, while CTD+ patients had fewer rare variants in COL3A1 than did CTD- patients.
In summary, rare variants in several collagen genes are particularly frequent in CM-1 cases and those in COL6A5 co-segregated with CM-1 in a Spanish multiplex family. COL6A5 has been previously associated with musculoskeletal phenotypes, but this is the first association with CM-1. This findings underscore the contribution of rare genetic variants in collagen genes to CM-1, and suggest that CM-1 in the presence and absence of CTD symptoms is driven by different genes 1)
How Should We Consider New Theories of Chiari Malformation Pathogenesis? 2).
Chiari I Malformation: Is It the Result of an instability, and Should We Perform a Fusion Surgery? 3).
CMI is characterized by underdevelopment of the occipital bone and posterior fossa (PF) and consequent cerebellar tonsillar herniation. The presence for a genetic basis to CMI is supported by many lines of evidence. The cellular and molecular mechanisms leading to CM1 are poorly understood. The occipital bone formation is dependent on complex interactions between genes and molecules with pathologies resulting from disruption of this delicate process. Whole exome sequencing of affected and not affected individuals from two Italian families with non-isolated CMI was undertaken. Single nucleotide and short insertion-deletion variants were prioritized using KGGSeq knowledge-based platform.
Merello et al., identified three heterozygous missense mutation variants: DKK1 c.121G>A (p.(A41T)) in the first family, and the LRP4 c.2552C>G (p.(T851R)) and BMP1 c.941G>A (p.(R314H)) in the second family. The variants were located at highly conserved residues, segregated with the disease, but they were not observed in 100 unaffected in-house controls. DKK1 encodes for a potent soluble WNT inhibitor that binds to LRP5 and LRP6, and is itself regulated by bone morphogenetic proteins (BMPs). DKK1 is required for embryonic head development and patterning. LRP4 is a novel osteoblast expressed receptor for DKK1 and a WNT and BMP 4 pathways integrator. Screening of DKK1 in a cohort of 65 CMI sporadic patients identified another missense variant, the c.359G>T (p.(R120L)), in two unrelated patients. These findings implicated the WNT signaling in the correct development of the cranial mesenchyme originating the PF 4).
The innate bony dysontogenesis in patients with CMI contributes to tonsilar ectopia and exacerbates CSF flow obstruction. A pressure gradient that existed between syringomyelia(SM) and SAS supports the perivascular space theory that is used to explain SM formation. Our findings demonstrate that phase-contrast magnetic resonance imaging (PCMR) maybe a useful tool for predicting patient prognosis 5).
In adult CIM, most tonsillar herniations are asymmetrical and most syringomyelia is eccentrical. The dominant side of tonsillar herniation determines the side of syrinx deviation, which in turn determines the main side of clinical presentations and the convex side of scoliosis. The results suggest that the more the descended tonsil tilts to one side, the more the syrinx tilts to the same side 6).