chloelogoa

Mucopolysaccharidosis Type VII

MPS VII (Sly disease)
 talalogoa


MPS VII is one of the least common forms of the mucopolysaccharidoses.  Mucopolysaccharidosis type VII (MPS-VII) or Sly disease is an inherited autosomal recessive Lysosomal Storage Disease (LSD). The disorder is caused by deficiency of the enzyme beta-glucuronidase (GUSB).  It is characterized by the inability to degrade glucuronic acid-containing GAGs (e.g dermatan sulfate, heparan sulfate, and chondroitin sulfate).  In its rarest form MPS VII causes puppies to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body.   Neurological symptoms may include mild to moderate mental retardation, communicating hydrocephalus, nerve entrapment, ocular impairment such as corneal clouding, and some loss of peripheral and night vision. Other symptoms include short stature, some skeletal irregularities, joint stiffness and restricted movement, and umbilical and/or inguinal hernias.

Treatment involves regular intravenous injections of a retrovirus encoding the enzyme (enzyme replacement therapy.)  This enables the dogs to start producing the enzyme themselves and they remain healthy and mobile.  This approach may be prohibitively expensive. 
 
The genetic test (SNP test)  for this disease is directed to the gene that codes for the enzyme b-glucuronidase.

Dog breeds most affected by this disorder are the German Shepherd as well as many types of Mixed Breed dogs.  If they reach adult hood affected dogs should not be bred.

Haskins and colleagues (1984) were the first to identify and characterize an animal model of MPS-VII in German shepherd dogs, whose pathologic features of the disease are very similar to those of humans except that the hepatosplenomegaly is less pronounced and the extent of mental retardation cannot be assessed. MPS-VII dogs have a single nucleotide substitution in the GUSB gene, which results in a guanine to adenine base change at nucleotide position 559 in the canine cDNA sequence, which in turn causes an arginine to histidine substitution at amino acid 166 in the canine GUSB (cGUSB) protein (Ray et al. 1998). The feline MPS-VII model has a missense mutation, specifically a guanine to adenine transition, that results in the change of glutamic acid to lysine at position 351 of the protein, eliminating GUSB enzymatic activity (Fyfe et al. 1999).   The development of successful gene therapy strategies for MPS-VII in the mouse model led to the testing of multiple gene therapy strategies in the dog and cat models. Researchers have reported clinical improvements in MPS-VII dogs that received canine GUSB-expressing retrovirus vectors (RV) as neonates (Ponder et al. 2002; Wang et al. 2006). Because studies in MPS-VII mice had shown that high levels of enzyme can be secreted by the liver and substantially improve clinical symptoms (Kosuga et al. 2000; Ohashi et al. 1997), two dogs in the 2002 study by Ponder and colleagues received human hepatocyte growth factor (HGF), which can induce canine hepatocyte replication (Kobayashi et al. 1996), in addition to RV-GUSB, while five dogs received RV-GUSB alone. All seven dogs showed similar clinical improvements at 6 to 17 months after treatment, although those that also received hepatocyte growth factor had much higher serum GUSB levels. All of the treated animals had bone and joint improvements, little or no corneal clouding, and no mitral valve thickening (Ponder et al. 2002). A follow-up study reported that the RV-GUSB-treated dogs maintained improved facial morphology, reduced lysosomal storage in osteocytes and synovium, and stable serum GUSB activity levels after 3 years (Mango et al. 2004). In addition, an assessment of the cardiovascular and skeletal features of the dogs several years after RV-GUSB treatment showed increased cervical vertebrae (C2) and femur lengths compared to untreated animals, although neither was as long as those of normal animals (Herati et al. 2008). A subsequent study called for the treatment of MPS-VII-affected dogs with the same RV-GUSB vector and monitoring of its effect on their cardiovascular disease (Sleeper et al. 2004); all of the dogs showed marked improvements in this area. In addition, after RV-GUSB, animals showed correction in both mitral regurgitation and mitral valve thickening.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2712138

 
Mucopolysaccharidosis VII is a lysosomal storage disease in which there is a buildup (storage) of mucopolysaccharides (glycosaminoglycans), due to the lack of the lysosomal enzyme acid hydrolase beta-glucuronidase (EC 3.2.1.31).
Summary
Ray et al. (1998) showed that this lysosomal storage disease in dogs is due to a single base substitution (G559A) in the gene for beta-glucuronidase, resulting in a single amino-acid substitution (Arg166His). These same authors were able to correct the enzyme deficiency in a cell line from an affected dog by means of a retroviral vector containing the normal gene.  http://omia.angis.org.au/retrieve.shtml?pid=1258

The gene therapy research of Drs. Haskins, Ponder and collaborators involving MPS VII dogs has significant implications for all MPS disorders.  In these experiments, two- to three-day-old dogs with MPS VII received four simple intravenous injections of a retroviral vector expressing canine beta-glucuronidase. The vector used was made from the Moloney murine leukemia virus with a liver-specific promoter; at several days of age, canine liver growth is so rapid that transduction occurs readily and beta-glucuronidase is secreted continuously into the bloodstream.
The enzyme's activity was subsequently found at normal, stable levels for up to 14 months in the treated dogs; one dog has produced 60 times normal enzyme for 17 months. Unlike other dogs with MPS VII, the treated dogs gained weight normally, attaining nearly 90 percent the weight of their unaffected littermates, and avoided the serious side effects normally associated with lysosomal storage diseases. The beta-glucuronidase gene does not appear to have been inserted into the germ line.



Mucopolysaccharidosis type VII in a German Shepherd Dog.







chloebutton     talabutton

The above information is simply informational. It's intent is not to replace the advice of a veterinarian nor to assist you in making a diagnosis of your pet. Please consult with your own veterinarian for confirmation of any diagnosis. Your pets life may depend on it.