Mucopolysaccharide Storage Disease in Three Families of Cats with Arylsulfatase B Deficiency: Leukocyte Studies and Carrier Identification

Haskins, Mark E.; Jezyk, Peter F.; Patterson, Donald F.

doi:10.1203/00006450-197911000-00001

Cited by 62 publications

(49 citation statements)

References 13 publications

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“…Biochemical, histological, and clinical analysis of these cats suggests that the entire range of MPS VI phenotypes from severe to mild are clustered within a narrow range of residual 4S activity in cultured skin fibroblasts from 0.5% to 4.6% of normal levels. L476P homozygous cats, which display a clinically severe MPS VI phenotype, contain very low levels of 4S activity in cultured skin fibroblasts (Table I), excrete substantially elevated levels of DS in their urine, show extensive lysosomal vacuolation in a large number of tissues including chondrocytes, and display severe degenerative joint disease (5,8). Despite the presence of residual 4S activity (approximately 3.1% of normal 4S activity levels in cultured skin fibroblasts, Table I), adult D520N/L476P compound heterozygous cats contain marginally elevated levels of DS in their urine and increased lysosomal vacuolation in most chondrocytes, which is associated with variable degrees of degenerative joint disease.…”

Section: Discussionmentioning

confidence: 99%

“…Screening the MPS VI Cat Colony for L476P and D520N-All animals used in these studies were established from heterozygous cats (MPS VI-3 family) obtained from Mark Haskins (University of Pennsylvania, Philadelphia, PA) (5). PCR products encoding f4S cDNA nucleotides 1353-1649 were amplified from cat venous blood using oligonucleotides f4S-7 and f4S-9 and Taq DNA polymerase (Boehringer Mannheim) as described previously (10).…”

Section: Methodsmentioning

confidence: 99%

“…A naturally occurring feline model for a severe form of MPS VI has previously been described (5), and a colony has been established in Adelaide to study the progression of the disease and evaluate the efficacy of therapy protocols. The intravenous administration of recombinant human 4S (rh4S) to severely affected MPS VI cats has been shown to dramatically reduce disease progression in a dose-dependent manner (6, 7).…”

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Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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The missense mutation, L476P, in the N-acetylgalactosamine 4-sulfatase (4S) gene, has previously been shown to be associated with a severe feline mucopolysaccharidosis type VI (MPS VI) phenotype. The present study describes a second mutation, D520N, in the same MPS VI cat colony, which is inherited independently of L476P and is associated with a clinically mild MPS VI phenotype in D520N/L476P compound heterozygous cats. Biochemical and clinical assessment of L476P homozygous, D520N/L476P compound heterozygous, and D520N homozygous cats demonstrated that the entire range of clinical phenotypes, from severe MPS VI, to mild MPS VI, to normal are clustered within a narrow range of residual 4S activity from 0.5% to 4.6% of normal levels. When overexpressed in CHO-KI cells, the secreted form of D520N 4S was inactivated in neutral pH conditions. In addition, intracellular D520N 4S protein was rapidly degraded and corresponded to 37%, 14.5%, and 0.67% of normal 4S protein levels in the microsomal, endosomal, and lysosomal compartments, respectively. However, the specific activity of lysosomal D520N 4S was elevated 22.5-fold when compared with wild-type 4S. These results suggest that the D520N mutation causes a rapid degradation of 4S protein. The effect of this is partially ameliorated as a result of a significant elevation in the specific activity of mutant D520N 4S reaching the lysosomal compartment. The mucopolysaccharidoses (MPS)1 are a group of lysosomal storage disorders that involve the deficiency of specific enzymes required for the degradation of glycosaminoglycans (GAG). MPS VI is characterized by a deficiency of N-acetylgalactosamine 4-sulfatase (4S), which leads to the lysosomal accumulation and urinary excretion of the GAG dermatan sulfate (DS) (1). The severe MPS VI phenotype is characterized by growth retardation, coarse facial features, joint stiffness, corneal clouding, skeletal deformities, and organ and soft tissue involvement. As a result of DS storage in the heart valve and lung, the normal function of these organs is often compromised, leading to early death in affected individuals. The central nervous system does not appear to be affected, even in individuals with clinically severe MPS VI (2).Patients with MPS VI are diagnosed by elevated levels of DS in their urine and a substantial reduction or lack of 4S activity in cells such as peripheral blood leukocytes and cultured skin fibroblasts. The clinical phenotype of MPS VI patients ranges from severe to relatively mild and has generally been shown to correlate with urinary DS and residual 4S activity levels (2). Generally, patients manifest symptomology associated with MPS VI when their 4S protein and activity levels are 5% or less of normal controls (3).Currently, there is no safe and effective treatment available for MPS patients other than surgical intervention to alleviate symptoms whenever possible. MPS VI is a good candidate for both enzyme and gene replacement therapy protocols for a number of reasons. First, the complication of targeting r...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Mild Feline Mucopolysaccharidosis Type VI

Yogalingam

Hopwood

Crawley

et al. 1998

Journal of Biological Chemistry

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“…A variety of gross pathologic lesions indicative of DJD are commonly encountered in the joints of MPS VI cats older than 6 mo of age (5,6). In younger MPS VI cats (12-15 wk of age; open physes), radiographs of joints indicate irregular subchondral bone contour and increased joint space (5,7,8). Vacuolation of chondrocytes is the most striking histologic feature of cartilage samples obtained from MPS VI cats at various ages (9,10) and is already present in the mid-term fetus (5).…”

Section: Ps VI (Maroteaux-lamy Syndrome) Is a Lysosomalmentioning

confidence: 99%

Intra-Articular Enzyme Administration for Joint Disease in Feline Mucopolysaccharidosis VI: Enzyme Dose and Interval

et al. 2006

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Degenerative joint changes have been reported in human mucopolysaccharidosis VI (MPS VI) and are a prominent feature of feline MPS VI. Joint disease has proven refractory to intravenous enzyme replacement therapy (ERT) in the MPS VI cat because enzyme is unable to reach cells in cartilage. In this study, enzyme was infused directly into the intraarticular space to determine whether joint tissues are able to respond to replacement enzyme. Clearance of glycosaminoglycans from chondrocytes was observed at a dose of 10 g recombinant human N-acetylgalactosamine-4-sulfatase (rh4S), but greater clearance was observed with higher doses. The chondrocytes at the articular surface were cleared preferentially. Lysosomal vacuolation in cruciate ligament and synovial cells also decreased upon addition of rh4S. One month after injection of rh4S, a slight reaccumulation of storage was observed at the surface of the joint, but extensive reaccumulation was observed 2 mo after injection. These results indicate that by bypassing the synovium using intraarticular ERT, significant reduction in storage material in joint tissues can be achieved. Localized ERT in the joint space provides a mechanism for delivering enzyme directly to the articular cartilage and a potential therapy for joint pathology in MPS VI.

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“…All reference polysaccharides, enzymes, enzyme substrates, and other biochemicals were purchased from Sigma Chemical Co., St. Louis, MO. Leukocytes were separated from fresh heparinized blood by 0.03 dextran centrifugation as described previously (18). Leukocytes from aliquots of some blood samples were enriched to 0.8-0.9 lymphocytes by gradient centrifugation in Ficoll-Hypaque (19).…”

Section: Animalsmentioning

confidence: 99%

Glycogen Storage Disease Type IV: Inherited Deficiency of Branching Enzyme Activity in Cats

et al. 1992

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ABSTRACT. Glycogen storage disease type IV due to branching enzyme deficiency was found in an inbred family of Norwegian forest cats, an uncommon breed of domestic cats. Skeletal muscle, heart, and CNS degeneration were clinically apparent and histologically evident in affected cats older than 5 mo of age, but cirrhosis and hepatic failure, hallmarks of the human disorder, were absent. Beginning at or before birth, affected cats accumulated an abnormal glycogen in many tissues that was determined by histochemical, enzymatic, and spectral analysis to be a poorly branched C Y -~,~-D -~~U C~I I .Branching enzyme activity was less than 0.1 of normal in liver and muscle of affected cats and partially deficient (0.17-0.75 of normal) in muscle and leukocytes of the parents of affected cats. These data and pedigree analysis indicate that branching enzyme deficiency is a simple autosomal recessive trait in this family. This is the first reported animal model of human glycogen storage disease type IV. Glycogen storage disease type IV (Andersen disease, amylopectinosis, McKusick catalogue no. 232500) is a rare, inherited disorder of glycogen metabolism in humans caused by deficiency of a-1,4 glucan: a-1,4 glucan 6-glycosyl transferase (EC 2.4.1. 18), the glycogen branching enzyme (1-5). An abnormal glycogen that superficially resembles amylopectin, containing longer chain lengths and fewer branch points than normal glycogen (2, 6, 7), is found in skeletal, smooth, and cardiac muscle, central and peripheral nervous systems, liver, and cells of the reticuloendothelial system (1, 2, 8, 9). Fewer than 50 patients with biochemically confirmed glycogen storage disease type IV have been reported. Most affected children fail to thrive before 1 y of age and die from cirrhosis and the sequelae of hepatic failure between 1 and 4 y of age. Some children exhibit signs of cardiac failure or neuromuscular involvement, with or without signs of hepatic disease (8, 10, 1 I), and a few patients with later onset of signs and longer survival have been reported (10,12,13). Orthotopic liver transplantation has been life-saving in a few patients (14). Biochemical evidence and family pedigrees indicate that type IV glycogen storage disease is inherited as an autosomal recessive trait; heterozygote detection and successful prenatal diagnosis have been reported (12,15,16,17). This report describes the clinical, pathologic, biochemical, and genetic characteristics of glycogen storage disease type IV in a family of purebred domestic cats. MATERIALS AND METHODS Animals.Affected cats and their family members were clientowned animals. Unrelated control cats were chosen from colonies maintained by the University of Pennsylvania Unit of Laboratory Animal Resources. All animal-use protocols were approved by the Institutional Animal Care and Use Committee of the University and conformed to National Institutes of Health guidelines.Histopathology and electron microscopy. Tissues for light microscopy were fixed in 1.25 M neutral buffered formaldehyde (10% forma...

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Mucopolysaccharide Storage Disease in Three Families of Cats with Arylsulfatase B Deficiency: Leukocyte Studies and Carrier Identification

Cited by 62 publications

References 13 publications

Mild Feline Mucopolysaccharidosis Type VI

Mild Feline Mucopolysaccharidosis Type VI

Intra-Articular Enzyme Administration for Joint Disease in Feline Mucopolysaccharidosis VI: Enzyme Dose and Interval

Glycogen Storage Disease Type IV: Inherited Deficiency of Branching Enzyme Activity in Cats

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