Date of Award
8-2026
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Healthcare Genetics
Committee Chair/Advisor
Dr. Sara Sarasua
Committee Member
Dr. Luigi Boccuto
Committee Member
Dr. Christopher Farrell
Committee Member
Dr. Tracy Lowe
Abstract
Rare diseases impact approximately 10% of the people in the United States, yet 95% of rare diseases still do not have an approved treatment option available. Additionally, medical management of rare diseases is complicated by the fact that a large knowledge gap for these disorders exists in the medical community. In fact, the average person with a rare disease waits 5-7 years for a diagnosis, a phenomenon known as the diagnostic odyssey. Recently described in the past 20 years, the polyaminopathies comprise 5 syndromes with causative genes in the polyamine pathway that have been described to date: Snyder-Robinson syndrome, Bachmann-Bupp syndrome, DHPS deficiency, Faundes-Banka syndrome, and DOHH disorder. Together, approximately 200 patients around the world have been diagnosed with a polyaminopathy, with 62 of those cases being described in the literature to date. Patients continue to be identified at a greater rate than ever, thanks to advances in and access to genetic testing; however, many medical providers remain unaware of these syndromes due to their ultra-rare nature and the limited number of publications and resources available regarding diagnosis and management of these diseases.
Knowledge gaps also exist within the scope of our understanding of the pathophysiology of rare diseases, largely because rare disease research has historically been underfunded. To bridge the gap in rare disease research, this dissertation first aimed to identify areas for improvement in the scope of federal funding for rare disease research by performing a policy analysis of the Orphan Drug Act and the Rare Diseases Act. As a result, recommendations for proposed changes to these policies were made to support increased support for rare disease research.
To address the gap in knowledge of rare diseases that exists within the clinical space, a critical narrative literature review was performed. Utilizing the Scale for the Assessment of Narrative Review Articles, 41 unique articles were identified to meet search criteria and were included in this review. These 41 manuscripts included case reports of 62 unique patients with a polyaminopathy diagnosis. This review analyzed the genetic and phenotypic features of the five polyaminopathies and identified unique, defining features of each syndrome, as well as overlapping features shared between all polyaminopathies.
Next, a novel zebrafish model system was established and characterized to advance our understanding of one specific polyaminopathy, Bachmann-Bupp syndrome. Bachmann-Bupp syndrome, caused by variants in ornithine decarboxylase 1 (ODC1), is the only polyaminopathy with a treatment option available; however, much is left to learn about the pathophysiology of the disease as well as the mechanism of action that this treatment has on improving biochemical and clinical phenotypes. Zebrafish are well-established models for human neurodevelopmental disorders and are, in many ways, much easier to work with than mice. Human ODC1 and zebrafish odc1 share a high degree of conservation, and the polyamine pathway acts in a similar manner between the two organisms. Using mRNA microinjection into the yolk of fertilized zebrafish ova to encode the premature truncating C-terminal variant from the index patient with Bachmann-Bupp syndrome, this novel model was established. Further characterization techniques identified that key features of human Bachmann-Bupp syndrome were mirrored in this in vivo model, including elevated ODC enzyme and putrescine levels, developmental delay, hypotonia, macrocephaly, macrosomia, and anxiety. Taken together, the work presented in this dissertation addresses major gaps in understanding and knowledge in the rare disease space, specifically in polyaminopathy research.
Recommended Citation
VanSickle, Elizabeth, "Bridging the Gap in Rare Disease Research: Clinical Characterization of the Polyaminopathies and the Development of a Novel Zebrafish Model for Bachmann-Bupp Syndrome" (2026). All Dissertations. 4383.
https://open.clemson.edu/all_dissertations/4383
Author ORCID Identifier
0000-0001-5504-9248