OMIA 000666-9685 : Mucopolysaccharidosis VI in Felis catus

In other species: dog

Possibly relevant human trait(s) and/or gene(s) (MIM number): 253200

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 1996

Cross-species summary: This disorder is a lysosomal storage disease, caused by a deficiency of the lysosomal enzyme N-acetylgalactosamine 4-sulfatase.

Species-specific description: Mucopolysaccharidosis type VI (MPS VI) is a lysosomal storage disease characterized by intracellular accumulation of the glycosaminoglycan dermatan sulfate. Signs first appear at 6 to 8 weeks of age. There are genetic tests available for two reported mutations.

Edited by Mark E Haskins, VMD, PhD

Mapping: FCA (A1)

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), Yogalingam et al. (1996) identified a base substitution at codon 476, c.1427T>C, giving rise to a substitution of proline for leucine (p.L476P), in the feline ARSB (arylsulfatase B) gene. The mutant peptide appears only as a precursor, and shows no functional activity. A second mutation, aspartic acid to asparagine substitution at codon 520 (c.1558G>A; D520N), was identified in the same family (Crawley et al. 1998), which originated in New Jersey.

Clinical features: The L476P homozygotes show dwarfism and facial dysmorphia due to epiphyseal dysplasia, whereas the other two genotypes (L476P/D520N heterozygotes and D520N homozygotes) show normal growth and appearance. Signs of severe disease first appear at 6 to 8 weeks of age . Affected cats have wide faces with shortened noses, small ears, and develop reduced cervical and lumbar spine flexibility (Cowell et al., 1976; Jezyk et al., 1977, Haskins et al., 1979). They grow more slowly than normal siblings and can develop hindlimb paresis or paralysis due to spinal cord compression prior to 8 months of age (Crawley et al., 2003). On radiographs, there is generalized osteopenia with a coarse trabecular pattern and severe epiphyseal dysplasia of the vertebrae. Signs of degenerative joint disease include irregular subchondral bone outlines and osteophyte development (Crawley et al., 2003). Affected animals are cognitively normal (Walkley et al., 2005).

Pathology: Affected cats are deficient in the lysosomal enzyme arylsulfatase B (also known as N-acetylgalactosamine 4-sulfatase). Dermatan sulfate accumulates intracellularly and is excreted in urine (Haskins et al., 1980). Cats homozygous for the L476P mutation develop severe skeletal disease, corneal clouding, heart valve thickening, and have prominent cytoplasmic granules in white blood cells. Cats homozygous for D520N do not develop clinically significant disease (Crawley et al., 2003), but have prominent cytoplasmic granules in white blood cells. Although affected cats accumulate gangliosides and unesterified cholesterol within individual pyramidal neurons, there are no noticeable neurologic deficits (Walkley et al., 2005). There is an analogous human condition (Maroteaux-Lamy syndrome, OMIM# 253200).

Prevalence: Allelic frequency of the L476P substitution is low in the general Siamese cat population, but is present across the USA, and has been reported in Italy and Eastern Europe. The disease has also been seen in non-Siamese cats (Haskins, personal communication). The allelic frequency of the D520N substitution is higher (11.4%) in the Siamese cat population (Crawley et al., 2003).

Control: Siblings of affected cats should be tested. Affected or carrier cats should not be bred.

Genetic testing: A timely warning has been issued by Lyons et al. (2016): "No health problems are associated with the D520N (c.1558G>A) variant, however, breeders that obtain positive results for this variant are speculating as to possible correlation with health concerns. Birman cats already have a markedly reduced gene pool and have a high frequency of the MPS VI D520N variant. Further reduction of the gene pool by eliminating cats that are heterozygous or homozygous for only the MPS VI D520N variant could lead to more inbreeding depression effects on the breed population. Herein is debated the genetic testing of the MPS VI D520N variant in cats. Surveys from different laboratories suggest the L476P (c.1427T>C) disease-associated variant should be monitored in the cat breed populations, particularly breeds with Siamese derivations and outcrosses. However, the D520N has no evidence of association with disease in cats and testing is not recommended in the absence of L476P genotyping. Selection against the D520N is not warranted in cat populations. More rigorous guidelines may be required to support the genetic testing of DNA variants in all animal species."

Breed: Siamese.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ARSB arylsulfatase B Felis catus A1 NC_018723.3 (145306338..145138361) ARSB Homologene, Ensembl, NCBI gene

Variants

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Siamese Mucopolysaccharidosis VI ARSB missense Felis_catus_6.2 A1 g.143229993T>C c.1427T>C p.L476P 1996 8910299 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2016 Lyons, L.A., Grahn, R.A., Genova, F., Beccaglia, M., Hopwood, J.J., Longeri, M. :
Mucopolysaccharidosis VI in cats - clarification regarding genetic testing. BMC Vet Res 12:136, 2016. Pubmed reference: 27370326. DOI: 10.1186/s12917-016-0764-y.
2015 Ruane, T., Haskins, M., Cheng, A., Wang, P., Aguirre, G., Knox, V.W., Qi, Y., Tompkins, T., O'Neill, C.A. :
Pharmacodynamics, pharmacokinetics and biodistribution of recombinant human N-acetylgalactosamine 4-sulfatase after 6months of therapy in cats using different IV infusion durations. Mol Genet Metab :, 2015. Pubmed reference: 26776148. DOI: 10.1016/j.ymgme.2015.10.006.
2012 Auclair, D., Finnie, J., Walkley, S.U., White, J., Nielsen, T., Fuller, M., Cheng, A., O'Neill, C.A., Hopwood, J.J. :
Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats. Pediatr Res 71:39-45, 2012. Pubmed reference: 22289849. DOI: 10.1038/pr.2011.13.
Ferla, R., O'Malley, T., Calcedo, R., O'Donnell, P., Wang, P., Cotugno, G., Claudiani, P., Wilson, J.M., Haskins, M.E., Auricchio, A. :
Gene therapy for MPS VI is effective in cats without pre-existing immunity to AAV8. Hum Gene Ther :, 2012. Pubmed reference: 23194248. DOI: 10.1089/hum.2012.179.
Ponder, K.P., O'Malley, T.M., Wang, P., O'Donnell, P.A., Traas, A.M., Knox, V.W., Aguirre, G.A., Ellinwood, N.M., Metcalf, J.A., Wang, B., Parkinson-Lawrence, E.J., Sleeper, M.M., Brooks, D.A., Hopwood, J.J., Haskins, M.E. :
Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats. Mol Ther 20:898-907, 2012. Pubmed reference: 22395531. DOI: 10.1038/mt.2012.9.
Sewell, A.C., Haskins, M.E., Giger, U. :
Dried blood spots for the enzymatic diagnosis of lysosomal storage diseases in dogs and cats. Vet Clin Pathol 41:548-57, 2012. Pubmed reference: 23121383. DOI: 10.1111/j.1939-165x.2012.00485.x.
2011 Cotugno, G., Annunziata, P., Tessitore, A., O'Malley, T., Capalbo, A., Faella, A., Bartolomeo, R., O'Donnell, P., Wang, P., Russo, F., Sleeper, M.M., Knox, V.W., Fernandez, S., Levanduski, L., Hopwood, J., De Leonibus, E., Haskins, M., Auricchio, A. :
Long-term amelioration of feline Mucopolysaccharidosis VI after AAV-mediated liver gene transfer. Mol Ther 19:461-9, 2011. Pubmed reference: 21119624. DOI: 10.1038/mt.2010.257.
2010 Auclair, D., Finnie, J., White, J., Nielsen, T., Fuller, M., Kakkis, E., Cheng, A., O'Neill, CA., Hopwood, JJ. :
Repeated intrathecal injections of recombinant human 4-sulphatase remove dural storage in mature mucopolysaccharidosis VI cats primed with a short-course tolerisation regimen. Mol Genet Metab 99:132-41, 2010. Pubmed reference: 19896877. DOI: 10.1016/j.ymgme.2009.10.002.
2008 Lischka, FW., Gomez, G., Yee, KK., Dankulich-Nagrudny, L., Lo, L., Haskins, ME., Rawson, NE. :
Altered olfactory epithelial structure and function in feline models of mucopolysaccharidoses I and VI. J Comp Neurol 511:360-72, 2008. Pubmed reference: 18803239. DOI: 10.1002/cne.21847.
Sleeper, MM., Kusiak, CM., Shofer, FS., O'Donnell, P., Bryan, C., Ponder, KP., Haskins, ME. :
Clinical characterization of cardiovascular abnormalities associated with feline mucopolysaccharidosis I and VI. J Inherit Metab Dis 31:424-31, 2008. Pubmed reference: 18509743. DOI: 10.1007/s10545-008-0821-1.
Tessitore, A., Faella, A., O'Malley, T., Cotugno, G., Doria, M., Kunieda, T., Matarese, G., Haskins, M., Auricchio, A. :
Biochemical, pathological, and skeletal improvement of mucopolysaccharidosis VI after gene transfer to liver but not to muscle. Mol Ther 16:30-7, 2008. Pubmed reference: 17955027. DOI: 10.1038/sj.mt.6300325.
2007 Auclair, D., Hopwood, JJ., Lemontt, JF., Chen, L., Byers, S. :
Long-term intra-articular administration of recombinant human N-acetylgalactosamine-4-sulfatase in feline mucopolysaccharidosis VI. Mol Genet Metab 91:352-61, 2007. Pubmed reference: 17544310. DOI: 10.1016/j.ymgme.2007.04.009.
2006 Auclair, D., Hein, LK., Hopwood, JJ., Byers, S. :
Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: enzyme dose and interval. Pediatr Res 59:538-43, 2006. Pubmed reference: 16549525. DOI: 10.1203/01.pdr.0000203090.41012.a6.
2005 Vinayak, A., Cross, AR., Newell, S. :
What is your diagnosis? Mucopolysaccharidosis (MPS) type VI. J Am Vet Med Assoc 226:351-2, 2005. Pubmed reference: 15825724.
Walkley, SU., Thrall, MA., Haskins, ME., Mitchell, TW., Wenger, DA., Brown, DE., Dial, S., Seim, H. :
Abnormal neuronal metabolism and storage in mucopolysaccharidosis type VI (Maroteaux-Lamy) disease. Neuropathol Appl Neurobiol 31:536-44, 2005. Pubmed reference: 16150124. DOI: 10.1111/j.1365-2990.2005.00675.x.
2004 Crawley, A., Ramsay, SL., Byers, S., Hopwood, J., Meikle, PJ. :
Monitoring dose response of enzyme replacement therapy in feline mucopolysaccharidosis type VI by tandem mass spectrometry. Pediatr Res 55:585-91, 2004. Pubmed reference: 14711884. DOI: 10.1203/01.PDR.0000113789.30640.5C.
2003 Auclair, D., Hopwood, JJ., Brooks, DA., Lemontt, JF., Crawley, AC. :
Replacement therapy in Mucopolysaccharidosis type VI: advantages of early onset of therapy. Mol Genet Metab 78:163-74, 2003. Pubmed reference: 12649061.
Crawley, A.C., Muntz, F.H., Haskins, M.E., Jones, B.R., Hopwood, J.J. :
Prevalence of mucopolysaccharidosis type VI mutations in Siamese cats Journal of Veterinary Internal Medicine 17:495-8, 2003. Pubmed reference: 12892300.
2002 Ho, T.T., Maguire, A.M., Aguirre, G.D., Surace, E.M., Anand, V., Zeng, Y., Salvetti, A., Hopwood, J.J., Haskins, M.E., Bennett, J. :
Phenotypic rescue after adeno-associated virus-mediated delivery of 4-sulfatase to the retinal pigment epithelium of feline mucopolysaccharidosis VI Journal of Gene Medicine 4:613-21, 2002. Pubmed reference: 12439853. DOI: 10.1002/jgm.302.
Macri, B., Marino, F., Mazzullo, G., Trusso, A., De, Maria, R., Amedeo, S., Divari, S., Castagnaro, M. :
Mucopolysaccharidosis VI in a Siamese/short-haired European cat Zentralblatt fur Veterinarmedizin - Reihe A 49:438-442, 2002.
2001 Simonaro, CM., Haskins, ME., Schuchman, EH. :
Articular chondrocytes from animals with a dermatan sulfate storage disease undergo a high rate of apoptosis and release nitric oxide and inflammatory cytokines: a possible mechanism underlying degenerative joint disease in the mucopolysaccharidoses. Lab Invest 81:1319-28, 2001. Pubmed reference: 11555679.
2000 Byers, S., Crawley, A.C., Brumfield, L.K., Nuttall, J.D., Hopwood, J.J. :
Enzyme replacement therapy in a feline model of MPS VI: Modification of enzyme structure and dose frequency Pediatric Research 47:743-749, 2000. Pubmed reference: 10832731.
1999 Bielicki, J., Crawley, A.C., Davey, R.C.A., Varnai, J.C., Hopwood, J.J. :
Advantages of using same species enzyme for replacement therapy in a feline model of mucopolysaccharidosis type VI Journal of Biological Chemistry 274:36335-36343, 1999. Pubmed reference: 10593925.
Nuttall, J.D., Brumfield, L.K., Fazzalari, N.L., Hopwood, J.J., Byers, S. :
Histomorphometric analysis of the tibial growth plate in a feline model of mucopolysaccharidosis type VI Calcified Tissue International 65:47-52, 1999. Pubmed reference: 10369733.
Turner, CT., Hopwood, JJ., Bond, CS., Brooks, DA. :
Immune response to enzyme replacement therapy: 4-sulfatase epitope reactivity of plasma antibodies from MPS VI cats. Mol Genet Metab 67:194-205, 1999. Pubmed reference: 10381327. DOI: 10.1006/mgme.1999.2859.
Yogalingam, G., Crawley, A., Hopwood, J.J., Anson, D.S. :
Evaluation of fibroblast-mediated gene therapy in a feline model of mucopolysaccharidosis type VI Biochimica et Biophysica Acta - Molecular Basis of Disease 1453:284-296, 1999.
Yogalingam, G., Muller, V., Hopwood, J.J., Anson, D.S. :
Regulation of N-acetylgalactosamine 4-sulfatase expression in retrovirus-transduced feline mucopolysaccharidosis type VI muscle cells. DNA Cell Biol 18:187-95, 1999. Pubmed reference: 10098600. DOI: 10.1089/104454999315402.
Yogalingam, G., Muller, V., Hopwood, J.J., Anson, D.S. :
Regulation of N-acetylgalactosamine 4-sulfatase expression in retrovirus-transduced feline mucopolysaccharidosis type VI muscle cells DNA & Cell Biology 18:187-195, 1999.
1998 Crawley, A.C., Yogalingam, G., Muller, V.J., Hopwood, J.J. :
Two mutations within a feline mucopolysaccharidosis type VI colony cause three different clinical phenotypes Journal of Clinical Investigation 101:109-119, 1998. Pubmed reference: 9421472. DOI: 10.1172/JCI935.
Yogalingam, G., Hopwood, J.J., Crawley, A., Anson, D.S. :
Mild feline mucopolysaccharidosis type VI - identification of an N-acetygalactosamine-4-sulfatase mutation causing instability and increased specific activity Journal of Biological Chemistry 273:13421-13429, 1998. Pubmed reference: 9593674.
1997 Brooks, D.A., King, B.M., Crawley, A.C., Byers, S., Hopwood, J.J. :
Enzyme replacement therapy in mucopolysaccharidosis vi - evidence for immune responses and altered efficacy of treatment in animal models Biochimica et Biophysica Acta - Molecular Basis of Disease 1361:203-216, 1997.
Byers, S., Nuttall, J.D., Crawley, A.C., Hopwood, J.J., Smith, K., Fazzalari, N.L. :
Effect of enzyme replacement therapy on bone formation in a feline model of mucopolysaccharidosis type VI Bone 21:425-431, 1997. Pubmed reference: 9356736.
Crawley, A.C., Niedzielski, K.H., Isaac, E.L., Davey, R.C.A., Byers, S., Hopwood, J.J. :
Enzyme replacement therapy from birth in a feline model of mucopolysaccharidosis type VI Journal of Clinical Investigation 99:651-662, 1997. Pubmed reference: 9045867. DOI: 10.1172/JCI119208.
Yogalingam, G., Bielicki, J., Hopwood, J.J., Anson, D.S. :
Feline mucopolysaccharidosis type VI - correction of glycosaminoglycan storage in myoblasts by retrovirus-mediated transfer of the feline n-acetylgalactosamine 4-sulfatase gene DNA & Cell Biology 16:1189-1194, 1997.
1996 Crawley, A.C., Brooks, D.A., Muller, V.J., Petersen, B.A., Isaac, E.L., Bielicki, J., King, B.M., Boulter, C.D., Moore, A.J., Fazzalari, N.L., Anson, D.S., Byers, S., Hopwood, J.J. :
Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome Journal of Clinical Investigation 97:1864-1873, 1996. Pubmed reference: 8621770. DOI: 10.1172/JCI118617.
Yogalingam, G., Litjens, T., Bielicki, J., Crawley, A.C., Muller, V., Anson, D.S., Hopwood, J.J. :
Feline mucopolysaccharidosis type VI - characterization of recombinant n-acetylgalactosamine 4-sulfatase and identification of a mutation causing the disease Journal of Biological Chemistry 271:27259-27265, 1996. Pubmed reference: 8910299.
1995 Abreu, S., Hayden, J., Berthold, P., Shapiro, I.M., Decker, S., Patterson, D., Haskins, M. :
Growth plate pathology in feline mucopolysaccharidosis VI Calcified Tissue International 57:185-190, 1995. Pubmed reference: 8574934.
Norrdin, R.W., Simske, S.J., Gaarde, S., Schwardt, J.D., Thrall, M.A. :
Bone changes in mucopolysaccharidosis vi in cats and the effects of bone marrow transplantation - mechanical testing of long bones Bone 17:485-489, 1995. Pubmed reference: 8579961.
Turner, A.S., Norrdin, R.W., Gaarde, S., Connally, H.E., Thrall, M.A. :
Bone mineral density in feline mucopolysaccharidosis VI measured using dual-energy X-ray absorptiometry Calcified Tissue International 57:191-195, 1995. Pubmed reference: 8574935.
1993 Beekman, G.K. :
Mucopolysaccharidosis-VI in a Kitten - A Case Report and Discussion of Feline Maroteaux-Lamy Syndrome Feline Practice 21:7-11, 1993.
Deluca, T., Minichiello, L., Leone, A., Dinatale, P. :
Preliminary Molecular Analysis of a Case of Feline Mucopolysaccharidosis-VI Biochemical and Biophysical Research Communications 196:1177-1182, 1993. Pubmed reference: 7504466.
Norrdin, R.W., Moffat, K.S., Thrall, M.A., Gasper, P.W. :
Characterization of Osteopenia in Feline Mucopolysaccharidosis-VI and Evaluation of Bone Marrow Transplantation Therapy Bone 14:361-367, 1993. Pubmed reference: 8363879.
1992 Haskins, M.E., Otis, E.J., Hayden, J.E., Jezyk, P.F., Stramm, L. :
Hepatic Storage of Glycosaminoglycans in Feline and Canine Models of Mucopolysaccharidose-I, Mucopolysaccharidose-VI, and Mucopolysaccharidose-VII Veterinary Pathology 29:112-119, 1992. Pubmed reference: 1632054.
1989 Alroy, J., Freden, G.O., Goyal, V., Raghavan, S.S., Schunk, K.L. :
Morphology of Leukocytes from Cats Affected with Alpha- Mannosidosis and Mucopolysaccharidosis-VI (MPS-VI) Veterinary Pathology 26:294-302, 1989. Pubmed reference: 2503918.
1981 McGovern, M.M., Vine, D.T., Haskins, M.E., Desnick, R.J. :
An improved method for heterozygote identification in feline and human mucopolysaccharidosis VI, arylsulfatase-B deficiency. Enzyme 26:206-10, 1981. Pubmed reference: 6113958.
1980 Haskins, M.E., Aguirre, G.D., Jezyk, P.F., Patterson, D.F. :
The pathology of the feline model of mucopolysaccharidosis VI. Am J Pathol 101:657-74, 1980. Pubmed reference: 6778219.
1979 Haskins, M.E., Jezyk, P.F., Patterson, D.F. :
Mucopolysaccharide storage disease in three families of cats with arylsulfatase B deficiency: leukocyte studies and carrier identification Pediatric Research 13:1203-1210, 1979. Pubmed reference: 229456.
1977 Jezyk, P.F., Haskins, M.E., Patterson, D.F., Mellman, W.J., Greenstein, M. :
Mucopolysaccharidosis in a cat with arylsulfatase B deficiency: a model of Maroteaux-Lamy syndrome. Science 198:834-6, 1977. Pubmed reference: 144321.
1976 Cowell, K.R., Jezyk, P.F., Haskins, M.E., Patterson, D.F. :
Mucopolysaccharidosis in a cat Journal of the American Veterinary Medical Association 169:334-339, 1976. Pubmed reference: 134013.

Edit History


  • Created by Frank Nicholas on 26 Nov 2007
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Vicki Meyers-Wallen on 27 Sep 2011
  • Changed by Vicki Meyers-Wallen on 28 Sep 2011
  • Changed by Frank Nicholas on 07 Oct 2011
  • Changed by Frank Nicholas on 09 Dec 2011
  • Changed by Frank Nicholas on 03 Sep 2012
  • Changed by Tosso Leeb on 29 May 2013
  • Changed by Frank Nicholas on 05 Aug 2016