Reactive Oxygen Species in the Development of Gonadal Failure in Late-Onset Transaldolase Deficiency

Background:

Transaldolase is an enzyme regulating NADPH and ribose 5-phosphate production in the pentose phosphate pathway (PPP). Previously 39 patients with transaldolase deficiency have been described. The presenting symptoms are hepato(spleno)megalia, anemia, thrombocytopenia, dysmorphic facial features, abnormal skin, cardiac abnormalities, intra uterine growth restriction and hypergonadotropic hypogonadism. Liver failure is the main cause of mortality. The mechanism causing hypogonadism is not fully understood. The TALDO1 gene is highly expressed in steroidogenic cells. There could be a combined effect of damage to the steroidogenic cells having a high demand for NADPH for steroidogenesis and regulation of reactive oxygen species (ROS), and toxic effects of intermediate metabolites of the PPP.

Clinical case:

A 15y male was referred to our clinic due to absence of pubertal development. He was known to have atrial septal defect, renal tubulopathy, dysmorphic facial features and transient elevation of liver enzymes. Lab results showed hypergonadotropic hypogonadism. Parents were of Jewish Indian heritage. Whole exome sequencing showed homozygosity for a novel T167M missense mutation in the TALDO1 gene. Both parents were heterozygote for this mutation. Fibroblasts from the patient showed an increased production of ROS, indicating an increased susceptibility to oxidative stress, and suggesting a possible effect of antioxidant treatment.

Conclusion:

This case demonstrates in vitro increase of ROS in cells with PPP defect due to transaldolase deficiency, presenting clinically with hypergonadotropic hypogonadism and atrial septal defect. Cellular damage due to high ROS levels is thus indicated as a possible mechanism for gonadal failure in transaldolase deficiency patients.