#253220
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| MUCOPOLYSACCHARIDOSIS TYPE VII | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| MPS VII; MPS7 SLY SYNDROME BETA-GLUCURONIDASE DEFICIENCY GUSB DEFICIENCY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Phenotypic Series | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because mucopolysaccharidosis type VII (MPS VII, MPS7) is caused by mutation in the gene encoding beta-glucuronidase (GUSB; 611499). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mucopolysaccharidosis type VII is an autosomal recessive lysosomal storage disease characterized by the inability to degrade glucuronic acid-containing glycosaminoglycans. The phenotype is highly variable, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse facies, and variable degrees of mental impairment (Shipley et al., 1993). MPS VII was the first autosomal mucopolysaccharidosis for which chromosomal assignment was achieved. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Sly et al. (1973) reported a boy with skeletal changes consistent with a mucopolysaccharidosis, hepatosplenomegaly, and granular inclusions in granulocytes. He had hernias, unusual facies, protruding sternum, thoracolumbar gibbus, vertebral deformities, and mental deficiency. Fibroblasts demonstrated deficiency of beta-glucuronidase activity, at less than 2% of control values. Both parents and several sibs of the mother showed an intermediate level of the enzyme. Shipley et al. (1993) provided follow-up of the patient reported by Sly et al. (1973). Additional features included cardiac valvular anomalies and progressive skeletal deformities of the thorax, spine, hip, and knee joints. He died suddenly at age 19 years, possibly of a cardiac arrhythmia. Gitzelmann et al. (1978) described 2 brothers in whom MPS VII was unusually mild. Asymptomatic thoracic kyphosis and mild scoliosis were the main clinical features. Hernia, hepatosplenomegaly, corneal clouding, and dwarfing were absent. Radiologic signs were mild, confined to the spine, and consisted of irregularities of upper and lower vertebral plates, of vertebral flattening and some osteophytic changes. Both patients excreted excessive amounts of acid mucopolysaccharides in urine. Both had granulations in polymorphonuclear cells and to a lesser degree in monocytes. Cultured skin fibroblasts also had metachromatic granules; they showed about 10% of normal beta-glucuronidase activity. The older brother, aged 19 years, was the oldest known case. Sewell et al. (1982) reported a 6-year-old Turkish girl with MPS VII who presented in infancy with facial asymmetry, deformed feet, and delayed motor development. At age 5 years, she had disproportionate dwarfism, sternal protrusion, kyphosis, scoliosis, and hypertrichosis. She had a small umbilical hernia and mild liver enlargement. Motor function was normal, but speech was delayed. Radiographic examination showed widening of the iliac wings and broad ribs. Beta-glucuronidase activity in serum was essentially absent, but was 5.6% of control values in cultured fibroblasts. In a review of reported cases, Sewell et al. (1982) suggested that MPS VII comprises 3 main clinical groups: an early severe lethal form (Beaudet et al., 1975); an 'intermediate' form with slight organomegaly and moderate skeletal anomalies (the patient reported by Sewell et al., 1982); and a very mild form in which patients present later and show longer survival (Gitzelmann et al., 1978). Pfeiffer et al. (1977) reported a girl with a mild form of MPS VII. Storch et al. (2003) provided a detailed clinical follow-up of this girl. The disorder was first diagnosed at the age of 7 years based on the clinical features of short stature, mild craniofacial dysmorphism, corneal opacity, a broad-based gait, and mild mental retardation. X-ray evaluation showed signs of dysostosis multiplex. Urinary excretion of total glycosaminoglycans was increased and consisted of dermatan, chondroitin, and heparan sulfate. Decreased beta-glucuronidase activity was found in serum, lymphocytes, and cultured skin fibroblasts. The patient completed her schooling for the mentally retarded and worked in her parents' business as a switchboard operator. By the age of 34 years, spasticity, especially of the upper limbs, had increased. Cervical MRI and CT scans showed a dense pseudoarthrosis with odontoid dysplasia, a hypoplastic atlantal arch, and narrowed intervertebral foramina in segments C2-C4. Anterior, and especially posterior, ligamentous structures in segments C1-C3 were thickened and caused spinal cord compression with central signal hypodensities. Surgical relief of the spinal cord compression was performed. At the age of 37 years, the patient was 146 cm tall and showed macrocephaly, mild facial dysmorphism, macroglossia, and prognathia. Corneal opacity was mild and had not progressed since the age of 5 years; hearing was normal. She also had sternal protrusion, thoracolumbar scoliosis, lumbar lordosis, and contractions of the large joints. Neurologic examination showed spastic tetraplegia with hyperactive deep tendon reflexes and positive Babinski signs. The patient died unexpectedly at the age of 37 years, presumably as a consequence of cardiac arrest. In this patient, Storch et al. (2003) identified compound heterozygosity for 2 mutations in the GUSB gene (611499.0013; 611499.0014). Stangenberg et al. (1992) and de Kremer et al. (1992) described phenotypic extremes in beta-glucuronidase deficiency: a case with fetal hydrops presenting at 18 weeks' gestation and a chronic oligosymptomatic variant in a 20-year-old male with severe skeletal dysplasia, respectively. In the former case the parents were first cousins and there had been 2 previous similar fetal deaths. In the latter case there was no hepatosplenomegaly, hernia, corneal clouding, or neurologic abnormalities. Although the patient had Alder-type granulations in his polymorphonuclear leukocytes, the urine did not contain a significant excess of mucopolysaccharides. The most striking changes of spondyloepiphyseal dysplasia were in the thoracic spine, with flattening and collapse in T7, T8, and T10 vertebral bodies, and in the femoral capital epiphyses, which showed irregularities and fragmentation. Walter-Nicolet et al. (2003) described a 1-year-old Algerian girl with MPS VII, born to consanguineous parents, who presented with nonimmune hydrops fetalis. She had facial dysmorphism, hepatosplenomegaly, and hypertrophic cardiomyopathy. The mother, aged 27, had experienced 2 unexplained spontaneous abortions at 18 and 12 weeks of gestation. Hydrops fetalis was discovered at 20 weeks' gestation with ascites, bilateral pleural effusion, and hydramnios. Brain ultrasound scan showed a moderate bilateral hydrocephalus confirmed by cerebral MRI. Clinical features noted at birth included facial dysmorphism with coarsened facies, hypertelorism, epicanthus, anti-mongoloid eyelids, short nose with anteversion of the nostrils; pterygium colli; and hepatosplenomegaly. Axial hypotonia and peripheral hypertonia were present. Echocardiography showed moderate hypertrophic cardiomyopathy. Brain ultrasound scan showed moderate ventricular dilatation at 9 and 11 mm with normal brain morphology. Skeletal radiography was normal. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By immunoassay, Bell et al. (1977) identified cross-reactive antigen in cultured fibroblasts from 4 unrelated patients with deficiency of beta-glucuronidase activity. Titration patterns suggested allelic heterogeneity. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Diagnosis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prenatal Diagnosis Lissens et al. (1991) described a case of beta-glucuronidase deficiency presenting as nonimmune hydrops fetalis diagnosed at 26 weeks of gestation. The deficiency was disclosed on cultured amniotic fluid cells and in fetal plasma and was confirmed post-abortion. In a second pregnancy, a normal beta-glucuronidase activity was found in extracts of chorionic villi obtained at 10 weeks of gestation. Kagie et al. (1992) demonstrated beta-glucuronidase deficiency as a cause of hydrops fetalis by study of the amniotic fluid obtained at 25 weeks' gestation. Van Eyndhoven et al. (1998) diagnosed beta-glucuronidase deficiency as the cause of nonimmune hydrops fetalis by enzymatic assay of chorionic villi. In their patient, hydrops fetalis had occurred in 2 previous pregnancies. Chorionic villus sampling performed in the eleventh week of the subsequent pregnancy indicated that the fetus was affected. After termination in the twelfth week, signs of early hydrops fetalis were observed. Van Dorpe et al. (1996) described a family in which 3 consecutive fetuses were affected. Striking ascites and fetal hydrops were noted in the first fetus, and the pregnancy was terminated. Microscopic study revealed prominently vacuolated Hofbauer cells in the placenta and foamy macrophages in liver, spleen, bone marrow, and other organs. Greatly reduced activity of beta-glucuronidase in cultured skin fibroblasts confirmed the diagnosis of MPS VII. Edema of the neck and back in the next pregnancy led to a presumptive diagnosis of MPS VII, which was confirmed by the finding of very low enzyme activity in chorionic villus cells. The morphologic manifestations were the same in all 3 cases. Van Dorpe et al. (1996) emphasized the significance of morphologic examination of the fetus and placenta for the diagnosis of MPS VII. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Management | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Yamada et al. (1998) reported that allogeneic bone marrow transplant in a 12-year-old Japanese girl with MPS VII resulted in improved motor function and activities of daily living, decreased upper respiratory and ear infections, but no improvement in cognitive function. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 unrelated Japanese patients with MPS VII, Tomatsu et al. (1991) identified 2 different homozygous mutations in the GUSB gene (611499.0001 and 611499.0002, respectively). Using RT-PCR-SSCP and direct sequencing to screen for mutations in the GUSB cDNA, Vervoort et al. (1996) studied 17 MPS VII patients with hydrops fetalis or early and severe clinical presentation. In addition to 6 of 12 previously reported mutations, they detected 14 novel mutations. The mutations in hydropic fetuses were widely scattered in the GUSB gene. Analysis of 3 polymorphic sites in the mutant alleles allowed exclusion of identity by descent for some recurrent mutations. Vervoort et al. (1997) identified 5 novel mutations in the GUSB gene in 5 MPS VII patients. Four patients presented with hydrops fetalis and 1 with an early infantile form of the disorder. Tomatsu et al. (2002) stated that more than 45 different mutations in the GUSB gene had been identified in patients with MPS VII, approximately 90% of which were point mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See 611499 for information on animal models of MPS VII. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Beaudet et al. (1974); Brot et al. (1974); Danes and Degnan (1974); Gehler et al. (1974); Glaser and Sly (1973); Guibaud et al. (1979); Hoyme et al. (1981); Lee et al. (1985); Meng et al. (2010); Nelson et al. (1982); Peterson et al. (1982); Schwartz et al. (2003); Sly et al. (1974); Vervoort et al. (1998); Vervoort et al. (1998); Vervoort et al. (1995); Vervoort et al. (1993); Wu and Sly (1993); Wu et al. (1994); Yamada et al. (1995) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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