How Should We Consider New Theories of Chiari Malformation Pathogenesis? 1).
Chiari I Malformation: Is It the Result of an instability, and Should We Perform a Fusion Surgery? 2).
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 3).
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 4).
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 5).