11/23. Recurrent fetal hydrops due to mucopolysaccharidoses type VII. hydrops fetalis is associated with a wide range of abnormalities. In about 20% of cases of non-immune fetal hydrops, no cause is found despite investigations including routine post-mortem examination and enzyme studies may be indicated to detect an underlying metabolic storage disease. Fetal hydrops due to mucopolysaccharidosis type VII is very rare and a prenatal diagnosis is not usually made. We report a case of mucopolysaccharidosis type VII presenting as recurrent fetal hydrops and review the clinico-pathological features of this disorder. ( info) |
| A phenotypically normal mother of a mucopolysaccharidosis vii child, is reported with an unusually low beta-glucuronidase activity. Low enzyme activity was systemic (6-10% of controls) and residual beta-glucuronidase in leukocytes had an apparently normal Km value. [35S]sulphate incorporation and chase assays in fibroblasts gave values similar to control cells. A normal excretion pattern of glycosaminoglycan was found in this woman's urine. Low enzymatic activity can be related to a non-pathological 'pseudodeficiency' allele for beta-glucuronidase; this woman appears to be an apparent compound heterozygote for this allele and mucopolysaccharidosis vii. Her next pregnancy was monitored by chorionic villus sampling and a heterozygous fetus was suspected. These studies stress the need for complete enzyme investigations of obligate carriers for mucopolysaccharidoses in order to prevent difficulties at prenatal analysis. ( info) |
13/23. Mutational studies in a patient with the hydrops fetalis form of mucopolysaccharidosis type VII. Four prior mutations have been reported in three patients with beta-glucuronidase deficiency mucopolysaccharidosis (MPS VII), none of whom had the severe, infantile, hydropic form of the disease. We identified two mutations in the first reported case of nonimmune hydropic MPS VII whose cultured fibroblasts had < 1% of residual activity. The first mutation was a C-->T transition at position 1061 of the cDNA in exon 6 that gave rise to an Ala-->Val substitution in codon 354 (A354V). The second was a C-->T transition at position 1831 in exon 12 that produced an Arg-->Trp substitution in codon 611 (R611W). Transient expression in COS-7 cells revealed that both mutant enzymes were synthesized as normal-size precursors in normal quantities, but both exhibited accelerated turnover. The expressed A354V enzyme had a t0.5 (half-life) of 33 hr (wild-type t0.5 > 60 hr) and a specific activity 35% of wild-type enzyme. The R611W enzyme had a t0.5 of 20 hr and no detectable catalytic activity. The t0.5 of enzyme produced on cotransfection with A354V and R611W was nearly identical to that of A354V alone. Mutant enzyme expressed in transfected murine MPS VII cells gave similar residual activities relative to the wild-type enzyme. In cos cells, the A354V monomers formed mixed tetramers with coexpressed rat monomers, but the product of R611W did not. The higher than expected activity, both in cos cells and in murine MPS VII cells expressing A354V, provides further evidence that overexpression can partially correct some beta-glucuronidase mutations, apparently by driving the folding reaction of monomers or the assembly into tetramers by mass action. ( info) |
| The postmortem biochemical and pathological findings in the first patient reported with mucopolysaccharidosis vii are described. Clinical, radiographic, and biochemical features of this 19-yr-old black man were initially reported in 1973 when, at age 2 1/2 yr his enzymatic defect, deficiency of beta-glucuronidase, was identified. The autopsy findings are now described with biochemical data further characterizing the enzyme deficiency and resultant glycosaminoglycan accumulation. He had dysostosis multiplex and extensive cardiovascular lesions including arterial stenosis, and marked fibrous thickening of the atrioventricular and aortic valves. Microscopic evidence of lysosomal storage was found in bone, cartilage, arteries and cardiac valves, liver, spleen, lymph nodes, eyes, adrenal, pituitary, and the central nervous system. In the brain, storage was localized to specific regions, primarily intraneuronal, and appeared ultrastructurally as delicate whorled filamentous accumulations in lysosomes. Similar filamentous storage also occurred in medial cells of the aorta. Multiple postmortem tissues contained only trace amounts of beta-glucuronidase and elevated glycosaminoglycans, predominantly chondroitin 4- and 6-sulfate. ( info) |
15/23. beta-glucuronidase deficiency: identification of an affected fetus with simultaneous sampling of chorionic villus and amniotic fluid. Four pregnancies at risk for mucopolysaccharidosis vii were monitored by chorionic villus sampling obtained in the first or second trimester of gestation. One fetus showed reduced beta-glucuronidase activity following simultaneous sampling of chorionic villus and amniotic fluid at 17 weeks of gestation. The pregnancy was terminated. Subsequent assay of beta-glucuronidase activity in the fetal tissues was consistent with a diagnosis of mucopolysaccharidosis vii, thus confirming that chorionic villus samples provide useful information for diagnosis of this condition. ( info) |
16/23. Foamy changes of placental cells in probable beta glucuronidase deficiency associated with hydrops fetalis. Mucopolysaccharidosis type VII (MPS VII, beta glucuronidase deficiency) has been described in association with non-immune hydrops fetalis. Three consecutive pregnancies in an itinerant family, which resulted in stillbirths caused by non-immune hydrops are described. The parents were closely related and there was a strong family history of storage disorders. The main clue to the diagnosis, however, came from the presence of pronounced foamy cytoplasmic change in the villous Hofbauer cells of the placenta. This raised the possibility of an inherited metabolic storage disorder. The parents were subsequently shown to have beta glucuronidase activities in the heterozygous range in leucocytes and fibroblasts which suggested that the non-immune hydrops was caused by beta glucuronidase deficiency. ( info) |
17/23. Lysosomal storage disorders in thailand: the Siriraj experience. Lysosomal storage disorders are a heterogeneous group of biochemical genetic disorders; currently 40-50 are known. The clinical phenotype is determined by the tissue distribution of the storage material and degree of enzyme deficiency. The genetic transmission is mostly autosomal recessive. Lysosomal storage disorders can be divided into three groups according to the major organ system pathology: (1) Primary involvement of the central nervous system without significant somatic or skeletal pathology. Disorders of grey matter, eg gangliosidosis and disorders of white matter eg the leucodystrophy are the most common; (2) Primary involvement of the reticuloendothelial system with or without associated neuropathology, eg Niemann-Pick disease and gaucher disease; (3) Multisystem involvement in which skeletal manifestations are prominent features. The mucopolysaccharidosis and mucolipidoses are the two major forms with this clinical phenotype. Lysosomal storage disorders identified at Siriraj Hospital are neuronal ceroid lipofuscinosis, GMI gangliosidosis, mucolipidosis II, Maroteaux-Lamy, sialidosis, Sly syndrome, Hunter syndrome, Morquio syndrome, gaucher disease, Niemann-Pick, sandhoff disease, Pompe's disease and many more. Most patients came from the provinces where consanguinity is common. Confirmation usually is done by enzyme assays using skin fibroblast culture or leucocytes. genetic counseling is extremely important and prenatal diagnosis is recommended to high-risk couple. ( info) |
18/23. beta-glucuronidase P408S, P415L mutations: evidence that both mutations combine to produce an MPS VII allele in certain Mexican patients. Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is an autosomal recessively inherited lysosomal storage disease caused by a deficiency in beta-glucuronidase. We identified and studied a novel allele containing two C-to-T transitions resulting in P408S and P415L alterations, which is present in homozygous state in one Mexican patient and in heterozygous state in another. None of the previous reports describing mutations in the MPS VII gene include Mexican patients. Expression of either of the mutations individually showed only modest effects on the properties of the enzyme. However, expression of the doubly mutant allele resulted in markedly reduced activity and rapid degradation in an early biosynthetic compartment. ( info) |
| Non-immune hydrops fetalis caused by beta-glucuronidase deficiency (mucopolysaccharidosis vii). Study of a family with 3 affected siblings. We describe a family case of beta-glucuronidase deficiency with 3 consecutively affected siblings. The three fetuses showed hydrops at a very early stage. In the first and second pregnancy the hydrops was visible on ultrasound scan in the first trimester. In the second pregnancy this was highly suggestive for recurrence. The diagnosis of mucopolysaccharidosis type VII was suggested after pathologic examination of the first fetus and placenta, and confirmed by deficient beta-glucuronidase activity in cultured skin fibroblasts. In the second, as well as in the third pregnancy a prenatal biochemical diagnosis was possible on cultured chorionic villus cells. The third pregnancy was terminated before hydrops was visible on ultrasound scan. Pathologic findings in the 3 fetuses were similar. Vacuolated macrophages were found in all tissues, but were most prominent in placenta, liver, lymph nodes and bone marrow. ( info) |
20/23. Mucopolysaccharidosis type VII associated with hydrops fetalis: histopathological and ultrastructural features with genetic implications. A case of mucopolysaccharidosis type VII (MPS VII, beta glucuronidase deficiency) causing fatal hydrops fetalis in the third trimester is presented. The diagnosis was suspected on histopathological examination by the presence of foam cells in many of the viscera and foamy change in the placental Hofbauer cells. Electron microscopy showed empty cytoplasmic inclusion bodies within macrophages and in the Hofbauer cells. Enzyme assay of cultured fibroblasts showed markedly deficient beta glucuronidase activity, thus confirming the diagnosis. A detailed and thorough histopathological examination of hydrops fetalis cases is important to detect subtle features of inherited metabolic disorders. Use of a structured necropsy protocol is recommended for cases of non-immune hydrops. Electron microscopy is a useful adjunct to light microscopy in cases where an inherited metabolic disorder is suspected. Precise necropsy diagnosis is important as there are implications for genetic counselling and possible prenatal diagnosis in subsequent pregnancies. ( info) |