Genetics of Chiari I Malformation. Syringomyelia is most often associated with Chiari I malformation. The process by which the Chiari I malformation develops is unknown. Ectopia of the cerebellar tonsils (through the foramen magnum at the base of the skull), which is the defining characteristic of the Chiari I malformation, may result because the posterior fossa does not develop normally. In a clinical study of families with multiple members affected by the Chiari I malformation, we are using magnetic resonance imaging of the brain to evaluate for Chiari I malformation and to measure the size of the osseous structures and volume of the posterior fossa. After phenotyping family members as being affected or unaffected by these traits, we collect DNA specimens from them for genotyping. Genotyping and phenotyping have been completed and linkage analysis and genome-wide association studies (GWAS) are being performed. Appearance of strong linkage peaks (genome-wide significance levels) in different families in different regions suggests genetic heterogeneity. The most significant finding was on chromosome 8, family 15 for the Chiari trait (p=0.000234, -log10(p)=3.631). Whole exome sequencing is being conducted in family 15 to discover alleles that contribute to the Chiari I trait. Targeted sequencing under the candidate linkage peaks is planned in an attempt to find a DNA polymorphism (mutation) that is associated with the Chiari trait. Finding one or more genetic loci that are associated with the Chiari I malformation would lead to a better understanding of the etiology of the Chiari I malformation. Treatment of Syringomyelia. A natural history study of patients with syringomyelia was initiated 3 years ago in which patients will be monitored annually for 5 years with neurological examinations, standard scales of pain and function, and MRI of the brain and spine. Patients receive specialized care for their condition, including surgery if necessary. This study will better define the outcome of patients with syringomyelia and will provide preliminary data to generate hypotheses for future hypothesis-driven studies. This year we reported a study that evaluated the morphologic features of the cerebellum and medulla oblongata before and 3-6 months after surgery in patients with Chiari I malformation and syringomyelia. After surgery that expands the posterior fossa, the abnormal shape of the cerebellum and medulla oblongata characteristic of the Chiari I malformation will change to a more normal appearance. These findings support the concept that the Chiari I malformation arises from lack of development of the posterior fossa rather than a primary neural abnormality. This year we published a clinical study of the pathophysiology of primary spinal syringomyelia, a type of syringomyelia not associated with Chiari I malformation. A preliminary finding was that obstruction of the spinal subarachnoid space in primary spinal syringomyelia was associated with enlarged cerebrospinal fluid (CSF) pressure waves superior to the obstruction. Successful surgery for primary spinal syringomyelia opened CSF pathways, reduced CSF pressure waves to normal and resolved syringomyelia, as had successful surgery in our studies of Chiari I-type syringomyelia. This association suggests that primary spinal syringomyelia and Chiari I-type syringomyelia arise from a similar mechanism.
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