Mucopolysaccharidosis, Type Ivb
A number sign (#) is used with this entry because mucopolysaccharidosis type IVB (Morquio syndrome B) is caused by mutation in the gene encoding beta-galactosidase (GLB1; 611458) on chromosome 3p22.
Morquio syndrome B is allelic to the various forms of GM1-gangliosidosis (see, e.g., 230500). The latter disorders show central nervous system involvement.
DescriptionMucopolysaccharidosis type IVB is an autosomal recessive disorder characterized by skeletal dysplasia and corneal clouding. There is no central nervous system involvement and intelligence is normal. There is increased urinary keratan sulfate excretion (Suzuki et al., 2001).
See mucopolysaccharidosis type IVA (253000), also known as Morquio syndrome A, a genetically distinct disorder with overlapping clinical features caused by mutation in the GALNS gene (612222) on chromosome 16q24.
There may also be a nonkeratansulfate-excreting form of Morquio syndrome, so-called type C (252300).
Clinical FeaturesO'Brien et al. (1976) reported a 14-year-old girl with spondyloepiphyseal dysplasia, corneal clouding, and beta-galactosidase deficiency. Radiographic features included flattening of the vertebral bodies and femoral heads, coxa valga, abnormal metacarpal epiphyses, and narrowed phalanges. Beta-galactosidase activity was less than 5% of normal and both unaffected parents had about 50% residual enzyme activity. She had no neurologic abnormalities, which distinguished the disorder from GM1-galactosidase types I and II (230500, 230600).
Arbisser et al. (1977) reported another 14-year-old girl with mild dysostosis multiplex, odontoid hypoplasia, short stature, cloudy corneas, and increased urinary keratan sulfate, but no detectable central nervous system abnormalities. At age 9 years, she had shown kyphosis, swinging gait, and hip pain. The increased keratan sulfate suggested Morquio syndrome A, but galactosamine-6-sulfate sulfatase (GALNS) activity was normal, and beta-galactosidase activity was decreased. Conjunctival biopsy showed intracytoplasmic vacuoles typical of a lysosomal storage disease. The patient's mother showed an intermediate level of beta-galactosidase; the father was not available for study. Arbisser et al. (1977) postulated that the deficiency of beta-galactosidase in this patient was responsible for inadequate degradation of keratan sulfate and the appearance of a milder form of the Morquio syndrome. The authors suggested the designation Morquio syndrome B (MPS IVB) to differentiate it from classic Morquio syndrome A.
Spranger (1977) commented that the 'unusual' form of Morquio syndrome described by Dale (1931) was similar to that described by Arbisser et al. (1977) and thus likely represented beta-galactosidase deficiency. Spranger (1977) also noted that failure to detect heparan sulfate activity in some patients may be due to technical problems or residual enzyme activity.
Groebe et al. (1980) reported 2 cases of Morquio syndrome due to beta-galactosidase deficiency. That beta-galactosidase was indeed the primary defect was indicated by the absence of an endogenous inhibitor and by the intermediate enzyme levels in parents.
Van Gemund et al. (1983) reported 3 Dutch sibs, born of consanguineous parents, with Morquio syndrome B and beta-galactosidase deficiency. Clinical features included dysplastic hip joints, thoracolumbar kyphosis, protruding sternum, progressive short stature, and corneal opacities. Radiographic studies showed platyspondyly with abnormal vertebral bodies.
Beck et al. (1987) described 3 sibs with Morquio syndrome B. They had short trunk dwarfism, dysplasia of the pelvis, and epiphyseal abnormalities. Intelligence was normal. All had profound deficiency of beta-galactosidase activity in cultured fibroblasts.
Giugliani et al. (1987) described a brother-sister pair with clinical, radiologic, and enzymatic evidence of Morquio syndrome B but with atypical mental regression. There were also some atypical properties of the residual beta-galactosidase activity. Giugliani et al. (1987) suggested that these findings indicated that further heterogeneity can result from mutation at the beta-galactosidase locus.
Biochemical FeaturesVan der Horst et al. (1983) showed that fibroblasts from patients with Morquio syndrome B contained normal numbers of beta-galactosidase molecules with a normal turnover, but strongly reduced catalytic activity per enzyme molecule. Abnormal affinity for several substrates was found, including no detectable affinity for keratan sulfate and oligosaccharides. In contrast, these affinities were normal for the beta-galactosidase in adult type GM1-gangliosidosis fibroblasts (230650). Cell hybridization studies demonstrated that MPS IVB and the infantile and adult forms of GM1-gangliosidosis belong to the same complementation group.
Molecular GeneticsIn 3 patients with Morquio syndrome B, Oshima et al. (1991) identified 3 different compound heterozygous mutations in the GLB1 gene (611458.0009-611458.0011).
In a 15-year-old Japanese boy who presented with Morquio syndrome B, Ishii et al. (1995) found compound heterozygosity for 2 mutations in the GLB1 gene (Y83H, 611458.0015 and R482C, 611458.0016).
In a French patient with Morquio syndrome B phenotype, Paschke et al. (2001) identified compound heterozygosity for 2 mutations in the GLB1 gene: T500A (611458.0020) and Q408P (611458.0021).
Genotype/Phenotype CorrelationsHinek et al. (2000) performed functional expression studies on several GLB1 mutations resulting in Morquio syndrome B (see, e.g., G438E, 611458.0018; T500A; W273L, 611458.0009; and R482H, 611458.0010). All of the mutations were located in the coding region common to the GLB1 lysosomal enzyme and its splice variant S-Gal/EBP (elastin-binding protein), and none of the mutant proteins expressed EBP. Functional studies indicated that the mutant proteins resulted in impaired secretion of tropoelastin and inability to assemble elastic fibers, resulting in impaired elastogenesis.