Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as ... Galactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (summary by d'Azzo et al., 2001).
Kleijer et al. (1979) made the prenatal diagnosis of galactosialidosis by measuring beta-galactosidase and neuraminidase activities in cultured amniotic fluid cells.
Goldberg et al. (1971) described 3 children (2 boys and a girl), in a Mexican family with first-cousin parents, who had a disorder characterized by dwarfism, gargoyle facies, mental retardation, seizures, corneal clouding, macular cherry red spot, beta-galactosidase ... Goldberg et al. (1971) described 3 children (2 boys and a girl), in a Mexican family with first-cousin parents, who had a disorder characterized by dwarfism, gargoyle facies, mental retardation, seizures, corneal clouding, macular cherry red spot, beta-galactosidase deficiency, dysostosis multiplex, and hearing loss. The absence of clinically enlarged viscera, vacuolated blood cells, and mucopolysacchariduria was likewise distinctive. Berard-Badier et al. (1970) had described a 17-year-old patient (case 3) who had corneal opacities, a cherry red spot, and the same type of vacuolation of the Kupffer cells as that in the family studied by Goldberg et al. (1971). Widespread hemangiomas, possibly like the angiokeratomas of Fabry disease (301500), were described by Loonen et al. (1984) in a Japanese man in his 30s. These, together with telangiectases of the conjunctiva, had been present from age 8 years. Ishibashi et al. (1984) concluded that angiokeratoma has been observed only in Japanese cases with combined beta-galactosidase and neuraminidase deficiency. Chitayat et al. (1988) described a male with juvenile galactosialidosis who presented at age 19 with hip arthralgia and for evaluation for possible spondyloepiphyseal dysplasia. He had facial 'coarseness,' corneal clouding, mitral and aortic regurgitation, and hepatosplenomegaly. Electron microscopy of skin biopsy and peripheral blood lymphocytes showed membrane-bound fibrillogranular inclusion. The urine showed elevated sialyloligosaccharides but no free sialic acid. Alpha-neuraminidase and beta-galactosidase were both low in fibroblasts. The patient did not have macular cherry red spots, neurologic abnormalities, or mental retardation. In a female patient described by Andria et al. (1981) and studied biochemically by Strisciuglio et al. (1984), Strisciuglio et al. (1990) described the natural history of late infantile onset galactosialidosis during the first 18 years of life. Clinical findings in the first months of life included somewhat coarse facial features and hepatosplenomegaly. Dysostosis multiplex was evident by age 2.5 years. Mitral and aortic valvular disease developed over the next few years and cardiac disease became the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurologic symptoms, cherry red spots, or intellectual deterioration during the first 18 years. At age 16, aortic valve replacement for aortic regurgitation was performed. Thomas et al. (1979) found deficiency of neuraminidase in cultured fibroblasts from Goldberg's original patient. Cases of combined deficiency have been reported by Lowden and O'Brien (1979), Hoogeveen et al. (1980), and Wenger et al. (1978). Although it was known whether the disorder was clinically indistinguishable from the sialidoses without deficiency of beta-galactosidase, its distinctness was indicated by complementation in heterokaryon experiments. No evidence of a structural mutation of beta-galactosidase was found (Hoeksema et al., 1980). In normal cells and GM1-gangliosidosis cells, beta-galactosidase has a half-life of about 10 days, whereas in the doubly deficient cells it has a half-life of less than 1 day. This reduction is due to enhanced degradation. Hoogeveen et al. (1981) showed that both enzyme activities could be restored by a 'corrective factor' of glycoprotein nature produced by normal fibroblasts and other mutant cells, including those of beta-galactosidase-deficient GM1-gangliosidosis. The form of deficiency of glycoprotein neuraminidase activity unassociated with beta-galactosidase deficiency (sialidosis I and mucolipidosis I) may have a defect in the structural gene for neuraminidase, whereas the form which combines neuraminidase and beta-galactosidase deficiencies appears to have a defect in a 32,000 dalton glycoprotein necessary for activation or proteolytic protection of these 2 enzymes (d'Azzo et al., 1982). Sakuraba et al. (1985) pointed out that in normal subjects serum beta-galactosidase activity is markedly increased in clotting blood but patients with galactosialidosis show only a slight increase of this enzyme activity. Patients with GM1-gangliosidosis (230500) show no increase in enzyme in clotting blood. In normal individuals and persons with galactosialidosis, enzyme is released from leukocytes. Anticoagulants suppress this release. Palmeri et al. (1986) found differences in the nature of the abnormality in 3 clinically distinct but presumably allelic forms of the disorder. In cells of the early-infantile type (usually associated with death soon after birth), the synthesis of the 52-kD precursor of the 32-kD 'protective protein' was markedly reduced. Absence of the latter protein explained the severe neuraminidase deficiency. In the juvenile-adult form, there was relatively more 52-kD precursor but no 32-kD protein could be detected. Cells of the late-infantile form had, besides a small amount of the 32-kD glycoprotein, an accumulation of the 52-kD precursor. Apparently, this protein was genetically altered in such a way that its further processing was impaired. In this mutant form, furthermore, treatment with leupeptin led to a 4- to 6-fold increase in residual neuraminidase activity and an increase of the 32-kD glycoprotein. Nanba et al. (1987) found that the protein concentrate of the culture medium of normal fibroblasts restored the activities of the deficient enzymes, beta-galactosidase and neuraminidase, in galactosialidosis cells. This effect was inhibited by an antiserum that recognized a 46-kD protein. Galjart et al. (1988) determined that a 'protective protein' cDNA (CTSA) recognized a 2-kb mRNA in normal cells that was not evident in fibroblasts of an early infantile galactosialidosis patient. Strisciuglio et al. (1988) demonstrated by immunoprecipitation experiments a reduced amount of the 32-kD 'protective protein' and a normal amount of its precursor in late infantile galactosialidosis fibroblasts, while neither of the 2 polypeptides were detectable in early infantile and juvenile/adult fibroblasts. They suggested from this and uptake studies that a block in the maturation of the protective protein is responsible for the late infantile type of galactosialidosis. Kleijer et al. (1996) surveyed 20 galactosialidosis patients with different clinical phenotypes. They tested cathepsin A activity in cultured fibroblasts derived from the patients and their obligate heterozygote parents. In 12 patients with the early infantile type of the disease, almost complete absence of cathepsin A activity was observed, whereas 8 patients with either delayed infantile or the juvenile/adult type had 2% to 5% residual activity. Highest levels (5%) were present in 2 patients with milder clinical manifestations and later onset of the disease. Heterozygous values for cathepsin A were reduced on average to half of normal levels. They showed that cathepsin A has considerable activity in chorionic villi and amniocytes and was deficient in amniocytes from a pregnancy with an affected fetus, indicating the relevance of cathepsin A assay for prenatal diagnosis of galactosialidosis. Landau et al. (1995) added galactosialidosis to the list of conditions that can cause nonimmune hydrops fetalis. Four pregnancies of a 22-year-old Bedouin woman produced a severely hydropic fetus in 1 case; her husband was a first cousin. The second pregnancy was terminated in the second trimester after ultrasound diagnosis of hydrops fetalis. The placenta showed marked accumulation of a mucoid material. The first and third pregnancies resulted in delivery of a preterm hydropic baby who died a few days after birth. During the fourth pregnancy, hydrops fetalis was diagnosed at 26 weeks. Following the spontaneous onset of labor at 32 weeks of gestation, a male hydropic baby was born by vaginal delivery. Physical examination showed massive ascites and edema of the limbs and genitalia. The face was notable for hematomata on the eyelids, coarse features, and a depressed nasal bridge. Both the liver and the spleen were palpable 4-5 cm below the costal margin. The infant was markedly hypotonic. Serum albumin was normal. Peritoneal drainage was performed twice during the first days of life. At 3 weeks of age, ascites reappeared, necessitating repeated peritoneal drainage. Thereafter, fluid continued to reaccumulate, and the infant died at 2 months of age following worsening respiratory neurologic status. Examination of the placenta showed the same mucoid material as was found in the placenta in the second pregnancy. Fibroblasts from a skin biopsy taken at 1 week of age showed no activity of sialidase and a low activity of beta-galactosidase, compatible with the diagnosis of galactosialidosis. A fifth pregnancy was monitored with chorionic villus sampling which at 10 weeks of gestation showed normal activity of both enzymes; the pregnancy ended in the delivery of a full-term healthy baby. Olcay et al. (1998) described what appeared to be the first reported instance of cytopenias in galactosialidosis. The patient was a 7-month-old boy in whom the diagnosis of galactosialidosis had previously been made by enzymatic methods in both leukocytes and fibroblasts. He was later found to have anemia and thrombocytopenia and evidence of hemophagocytosis of erythrocytes, thrombocytes, lymphocytes, and granulocytes by the foamy cells that develop in this disorder.
In a clinical and molecular analysis of 19 Japanese galactosialidosis patients from 15 unrelated families, Takano et al. (1991) found only 2 cases with generalized and severe manifestations of neonatal onset; the other 17 cases had late onset ... In a clinical and molecular analysis of 19 Japanese galactosialidosis patients from 15 unrelated families, Takano et al. (1991) found only 2 cases with generalized and severe manifestations of neonatal onset; the other 17 cases had late onset of neurologic manifestations. All 17 late-onset patients had a splice site mutation resulting in a deletion of exon 7 (EX7DEL; 613111.0002). Shimmoto et al. (1993) reviewed a total of 6 mutations in Japanese cases of galactosialidosis. Many of the patients were genetic compounds and, as with other lysosomal storage diseases, compound heterozygosity of a mutation without expression of any enzyme activity, such as Y395C (613111.0006), with a mutation that produced a small amount of normally spliced mRNA, e.g., EX7DEL, resulted in clinical manifestations of intermediate severity. Zhou et al. (1996) studied 8 patients with galactosialidosis who presented at different ages. All patients studied had PPCA mRNA. To identify the molecular lesions in the PPCA gene they used RT-PCR to amplify the entire coding sequence which was then sequenced. In the early-onset patients they detected 2 new mutations: val104 to met (613111.0009) and leu208 to pro (613111.0010). The second mutation present in one of the early-onset patients was gly411 to ser (613111.0011). A patient with juvenile/adult onset proved to be a compound heterozygote for a ser23-to-tyr mutation on one allele and a splice site mutation in intron 7 (613111.0002) on the other allele. The 5 patients with late infantile-onset galactosialidosis were genetically much more homogeneous, having either the phe412-to-val (613111.0001) or tyr221-to-asn (613111.0008) mutation. These mutations occurred either in the homozygous or compound heterozygous state and Zhou et al. (1996) considered them to be diagnostic for the late infantile phenotype. Zhou et al. (1996) determined that the main factor determining the clinical course in galactosialidosis patients is the lysosomal level of mutant PPCA. In 2 severely affected patients with early infantile onset, they identified 3 novel mutations, val104 to met, leu208 to pro, and gly411 to ser (613111.0011), that prevent the phosphorylation of the PPCA precursor and thereby its transport to the lysosome. Galactosialidosis patients with late infantile onset of disease had at least one allele that could be phosphorylated and transported to the lysosome. Zhou et al. (1996) noted that the met378-to-thr mutation (613111.0012), present in compound heterozygosity in one of the patients, represented the first example of a point mutation that generates a new asn-linked glycosylation site that is actually utilized. They noted further that the additional oligosaccharide chain likely affects the proper folding and compartmentalization of the mutant.