New Research Identifies Enzyme Deficiency as Cause of Rare Skeletal Disorder

A recent study has shed light on the underlying cause of Catel–Manzke syndrome, a rare genetic bone disorder characterized by shortened bones, heart defects, cleft palate, and finger malformations. The research suggests that the syndrome stems from a deficiency of an enzyme known as dTDP-D-glucose 4,6-dehydratase (TGDS), leading to a shortage of an important enzyme-rescue metabolite.

Enzymes are crucial for facilitating various cellular processes, but they can become inactivated due to genetic mutations, environmental factors, or errors in cellular function. When enzymes like TGDS are inactivated, vital biochemical pathways are disrupted, which can result in developmental abnormalities.

The study discovered that TGDS plays a significant role in sugar metabolism related to bone formation. It appears that in humans, TGDS produces UDP-4-keto-6-deoxyglucose, a key molecule that helps maintain the function of another enzyme, UXS1, responsible for synthesizing UDP-xylose. UDP-xylose is essential for producing glycosaminoglycans (GAGs), structural components necessary for healthy skeletal development.

Researchers observed that if TGDS is inactivated, the production of UDP-4-keto-6-deoxyglucose declines, impairing UXS1 activity and reducing UDP-xylose levels. This reduction hampers GAG synthesis, ultimately affecting bone growth and leading to the symptoms observed in Catel–Manzke syndrome.

Experimental evidence from both cell cultures and mouse models supported this hypothesis. Mice with inactivated TGDS exhibited signs similar to human patients, confirming the enzyme's critical role in skeletal development.

The study concluded that TGDS is vital for producing UDP-4-keto-6-deoxyglucose, which helps counteract the inactivation of UXS1 in a cell-specific manner. While further research is needed to develop diagnostic and therapeutic applications, understanding this pathway paves the way for improved management of the disorder and potentially other enzyme-related diseases.

These findings advance our understanding of the molecular basis of rare skeletal disorders and may facilitate better genetic diagnosis and counseling in the future, highlighting the importance of enzyme rescue metabolites in human development.

Source: https://medicalxpress.com/news/2025-08-rare-bone-disorder-deficiency-enzyme.html