Filippo Ingoglia, PhD: “Functional studies in creatine transporter deficiency”
SHORT SUMMARY
Dr. Filippo Ingoglia presented this poster at the 2024 CCDS Patient + Scientific Symposium, in Salt Lake City, Utah. The poster describes the development of a functional assay to diagnose creatine transporter deficiency using UPLC-MSMS system. The assay will allow for the confirmation of the diagnosis of CTD and possibly the identification of CTD patients with residual transport activity. The project was funded by ACD.
ABSTRACT
Creatine transporter deficiency (CTD) is an X-linked disorder caused by variants in the creatine transporter gene (SLC6A8) and characterized by intellectual disability, failure to thrive, speech delay, autistic-like behavior, and seizures. Affected patients have increased urine creatine/creatinine ratio and pathogenic variants in the SLC6A8 gene. Genetic testing can miss variants outside the coding region of the gene or detect missense variants of uncertain significance (VUSs). In such cases, a functional assay can be used to confirm the diagnosis. We are developing a new assay to measure creatine transport in fibroblasts using a stable isotope rather than radioactive creatine. Uptake in cells from patients with suspected creatine transporter deficiency will be compared to those of normal cells and cells with known pathogenic variants in the SLC6A8 gene. In addition, we will immortalize fibroblasts hemizygous for a null allele and express in them the normal SLC6A8 minigene and one in which VUS have been recreated. This assay will confirm the diagnosis of creatine transporter deficiency, determine whether there is residual creatine transport activity, and define the function of VUS without the need for a skin biopsy in each patient.