Enzyme replacement therapy prevents loss of bone and fat mass in murine homocystinuria

Skeletal and connective tissue defects are the most striking symptoms in patients suffering from

classical homocystinuria (HCU). Here, we determined body composition and bone mass in three

mouse models of HCU and assessed whether a long-term administration of enzyme replacement

therapy (ERT) corrected the phenotype. The mouse models of HCU were analyzed using dualenergy

X-ray absorptiometry and the data were complemented by plasma biochemical profiles.

Both the mouse model lacking CBS (KO) and the one expressing human CBS mutant transgene on

amouse CBS null background (I278T) showed marked bone loss and decreased weight mostly due

to a lower fat content comparedwith negative controls. In contrast, theHOmouse expressing the

human CBS WT transgene on a mouse CBS null background showed no such phenotype despite

similar plasma biochemical profile to the KOand I278T mice.More importantly, administration of

ERT rescued bone mass and changes in body composition in the KO mice treated since birth and

reversed bone loss and improved fat content in the I278T mice injected after the development of

clinical symptoms. Our study suggests that ERT for HCU may represent an effective way of preventing

the skeletal problems in patients without a restricted dietary regime.