Emily Durham, PhD
Research Engagement Director
TBCK Foundation
“Knowing what we don’t know: Merging research and advocacy for TBCK Syndrome”
TBCK Syndrome, a multisystem disorder that is characterized by pediatric neurodegeneration was first described in 2016 as a condition related to loss of function mutations in TBC1 domain-containing Kinase (TBCK). With about 120 patients world-wide, TBCK Syndrome is considered ultra-rare with a general prevalence of less than 1 in 1,000,000. Describing this condition has become a collaborative endeavor involving patient advocates around the globe, geneticists, cell biologists, anatomists, and basic scientists. Despite this diverse group, genotype-phenotype correlation remains elusive. Twenty-eight unique variants have been recorded for TBCK syndrome so far. These span the gene and protein domains, however despite variation in severity of disease being highlighted in the literature, beyond multiple individuals sharing a variant that causes a particularly severe disease state, correlations have yet to be found. Craniofacial phenotypes are reported in 53 of 73 patients depicted in the literature. Aberrant head shape is reported in 19 of 22 patients for which this parameter is reported. Of those, three individuals are reported as having microcephaly, seven with macrocephaly, five with brachycephaly, and three with turricephaly. As aberrations from the norm are more likely to be reported, it may be that there are trends in head shape within the TBCK Syndrome patient cohort that are missed because 75% of the time it is not noted at all. Beyond the struggle to accurately describe TBCK syndrome, there are efforts to properly model the condition. Aberration to skull form has been noted in mice recapitulating the p.R126X mutation commonly seen in TBCK Syndrome. Clearly, loss of TBCK impacts craniofacial development in mammals. For the TBCK community, more comprehensive data gathering, and careful assessment of craniofacial form could reduce the diagnostic odyssey for this ultra-rare disease. Use of next-generation phenotyping, which was created to augment clinical identification of specific findings may also improve diagnostic rates globally. Merging advocacy and research, tailoring investigation towards meaningful patient outcomes, and defining what we do not yet know provides a clear roadmap towards positive impact for the TBCK Community.
Friday June 27, 2025, 11:00AM-12:00PM, EAD-506
University of North Texas Health Science Center
Fort Worth, Texas