Prenatal glycolysis restoration can rescue myocardial hypoplasia caused by platelet isoform of phosphofructokinase 1(PFKP) deficiency

Background Congenital myocardial hypoplasia affects heart function in congenital heart diseases, but its causes and mechanisms are unclear. Methods: : Fetuses with myocardial hypoplasia were examined using echocardiography imaging and genetic testing. The identified pathogenic genes were genetically targeted to validate mechanistic findings. We used stem cells and transgenic mice to understand molecular mechanisms and applied Preimplantation Genetic Testing for monogenic defects to obtain healthy offspring. In addition, 1,300 genetic sequencing records were screened to understand the prevalence of the disease and deepen our understanding of myocardial hypoplasia treatment. Results This is the first study to link PFKP pathogenic variant to human myocardial hypoplasia. We found that PFKP deficiency decreased embryonic heart glycolysis, resulting in a thinning myocardial wall and impaired cardiac function, attributable to a decline in cardiomyocyte proliferation. The intrauterine supplement with Fructose 1,6-bisphosphate, a direct product of PFKP catalysis, can rescue the main myocardial phenotype of fetal mice. Assisted reproductive technology was used to prevent PFKP pathogenic variant transmission to offspring. Finally, one of the family lines (family 1) obtained a healthy offspring with a normal heart. Conclusions: PFKP plays a key role in regulating glycolysis during embryonic cardiac development. Addressing glycolytic defects is crucial for myocardial hypoplasia. We provide new insights that have implications for genetic interventions, prenatal screening, and targeted intervention strategies.