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### Abstract

1. Galactosialidosis (GS) is a lysosomal storage disease (LSD) belonging to the subgroup of the glycoproteinoses. The disease is associated with combined deficiency of β-galactosidase (β-GAL) and neuraminidase 1 (NEU1), which is secondary to a primary defect of the serine carboxypeptidase/protective protein cathepsin A (PPCA), and is transmitted as an autosomal recessive trait.

2. All patients have clinical manifestations typical of a lysosomal storage disease, including coarse facies, cherry-red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes in peripheral blood. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. Hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of important neurologic signs characterize the late infantile type. The majority of reported patients have the juvenile/adult form and are mainly of Japanese origin. Myoclonus, ataxia, angiokeratoma, cognitive disability, neurologic deterioration, absence of visceromegaly, and long survival are quite characteristic of this subtype.

3. Sialyloligosaccharides and glycopeptides accumulate in patients’ lysosomes and are excreted in their body fluids, hence the classification of the disease as a glycoproteinosis. Ultrastructural analysis of central, peripheral, and autonomic nervous systems, retina, liver, kidney, skin, and lymphocytes shows numerous membrane-bound vacuoles and, in some tissues, membranous cytoplasmic bodies.

4. The autosomal gene encoding human PPCA is localized on chromosome 20q13.1. Both PPCA cDNA and genomic sequences are routinely used to analyze the disease-causing mutations in patients with different clinical phenotypes. Mainly single-base substitutions or splice-junction defects have been identified to date. Correlation of genotype with disease severity has emerged from structure-function studies of the mutant enzyme.

5. Mammalian PPCA is a multifunctional enzyme with distinct protective and catalytic activities. It associates with β-GAL and NEU1 in an early biosynthetic compartment, which allows the 2 glycosidases to be correctly compartmentalized in lysosomes and become catalytically active and stable. PPCA is synthesized as a zymogen of 54 kDa that is processed at acidic pH into a 32/20-kDa, 2-chain, mature enzyme. It is active at both acidic and neutral pH and functions as cathepsin A/deamidase/esterase on a subset of neuropeptides, including substance P, oxytocin, and endothelin I. Cathepsin A activity has been found to be deficient in every patient with GS who has been tested.

6. The 3-dimensional structure of the PPCA precursor has been solved by a combination of molecular replacement and twofold density averaging. The structure revealed an unusual inactivation mechanism of the zymogen that explains how removal of the 2-kDa peptide triggers activation. A number of amino acid substitutions found in defective PPCA from different GS patients have been modeled in the 3-dimensional structure. There appears to be a significant correlation between the effect of each mutation on the integrity of protein structure and the general severity of the clinical phenotype.

7. The disease can be suspected in patients with clinical features of a lysosomal storage disease showing sialyloligosacchariduria on thin-layer chromatography. The demonstration of a combined deficiency of β-GAL and NEU1 in lymphocytes or cultured skin fibroblasts is the preferred ...

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