Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses

Mice with mucopolysaccharidosis type VII (MPS VII) are devoid of beta-glucu ronidase and accumulate glycosaminoglycans in lysosomes resulting in bone d ysplasia, learning disabilities, and decreased mobility. MPS VII males do n ot breed and, while MPS VII females occasionally mate with heterozygous mal es, they do not maintain their young postnatally. Heterozygous matings prod uce less than 25% MPS VII offspring, but until now it was unclear whether t his results from prenatal or postnatal losses. The administration of recomb inant beta-glucuronidase from birth significantly reduces glycosaminoglycan storage in most tissues, increases life span, and improves the animal's co gnitive ability and mobility. To determine whether reproductive failure is corrected by such therapy, male and female MPS VII mice were injected with enzyme at weekly intervals from birth to 5 wk of age (6xinj). Enzyme-replac ed MPS VII mice bred when mated together. The 6xinj MPS VII males mated rep eatedly until they were killed 135 d postinjection. All mated 6xinj MPS VII females gave birth to two litters, but maintained few of their young. Sele ctive loss of MPS VII offspring was observed in matings between heterozygot es. Analysis of 379 preterm fetuses from heterozygous matings showed a freq uency of 24.6% MPS VII pups, indicating that the decreased number of MPS VI I pups produced by mating heterozygotes results from postnatal losses. The ovaries of young adult MPS VII mice have follicles and corpora lutea, and t he testes generate sperm. Results suggest that the reproductive failure in MPS VII mice is related to impaired mobility and/or impaired cognitive func tion, and enzyme replacement restores mating capacity.