== Gross phenotypic appearance of a PPCA / mouse at 7 months of age, compared to a wild-type littermate. biotech companies to invest in the manufacturing of new therapeutics. Both ERT and gene therapy may become available to patients in the near future. Keywords: PPCA, CTSA, galactosialidosis, therapy, lysosomal storage disease == 1 . Galactosialidosis and PPCA: historical aspects == Galactosialidosis (GS) was first classified as a variant of GM1-gangliosidosis, a glycosphingolipid storage disease due to an isolated deficiency of the lysosomal -GAL1, 2 . Licochalcone C However , the high residual -GAL activity measured in GS fibroblasts (~1520% of control values) could not Licochalcone C account for the severe, early onset presentation of the symptoms in patients. Subsequently, the identification by Wenger et al. 3of undetectable NEU1 activity, in addition to the partial deficiency of -GAL, in fibroblasts from a patient described as variant of GM1-gangliosidosis defined GS as a separate clinical entity. At that time the disease was thought to be caused by a primary deficiency of NEU1. Yet, co-culturing of fibroblasts with a combined NEU1/-GAL deficiency with fibroblasts with an isolated NEU1 deficiency partially corrected NEU1 activity in the former cells, raising the possibility that a third gene product was involved in GS. The identity of this corrective factor secreted in the medium and capable of restoring NEU1 and -GAL activities in GS fibroblasts was eventually discovered fortuitously because of its physical association with -GAL4, 5. An antiserum raised against purified -GAL precipitated Licochalcone C this enzyme with three previously unknown proteins of 54-, 32-, 20-kDa from human fibroblasts5. Remarkably, these three proteins were absent in fibroblasts of a GS patient with a severe clinical presentation. It was soon apparent that the three proteins were the products of a single gene and that the 54-kDa polypeptide was in fact the uncleaved precursor of the 32- and 20-kDa proteins5. The 54-kDa precursor was also the form present extracellularly that once taken up by GS cells restored NEU1 SLC7A7 and -GAL activities and their lysosomal stability. These findings gave the first proof that deficiency of a protective protein secondarily affected both glycosidases, and reinforced the biochemical evidence that the three proteins physically associate to form a multienzyme complex. This discovery established GS as a disease distinctive from GM1-gangliosidosis and sialidosis. After the cloning of the protective protein cDNA, Galjart et al. 6demonstrated that some Licochalcone C of the early onset cases of GS lacked the protective protein mRNA and identified the homology of the protein with serine proteases. Independently, the group of Ervin Erds7confirmed that the protective protein was indeed a serine protease with carboxypeptidase/deamidase/esterase activity (see below). Together these findings proved unequivocally the nature of the primary defect in GS. == 2 . GS: Clinical Phenotypes == GS is a prototypical lysosomal storage disease (LSD) of glycoprotein catabolism, which is inherited as an autosomal recessive trait. The disease is rare, although its prevalence is currently unknown. GS is one of the few LSDs caused by a primary defect in one of the lysosomal cathepsins. However , the secondary severe loss of NEU1 activity probably accounts for most of the overt clinical manifestations seen in patients and for the disease pathogenesis. GS primarily affects cells of the reticuloendothelial system and can be suspected in children with features typical of a lysosomal disorder, such as coarse facies, macular cherry-red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes in peripheral blood8. Sialyloligosacchariduria is diagnostic of the disease but it is indistinguishable from that observed in patients with sialidosis,.