Mucopolysaccharidosis

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Deformed legs with crooked radiocarpal joints and prominent joint hyperlaxity especially in the hind limbs and a brachycephalic craniofacial morphology in a 4-week-old Brazilian Terrier puppy[1]
Corneal opacity in a 2.5-year-old Miniature Poodle-cross diagnosed with mucopolysaccharidosis type VI[2]

Mucopolysaccharidosis is a rare autosomal-recessive genetic disease characterized by deficiencies of lysosomal enzymes, leading to accumulation of glycoaminoglycans (GAG) in many tissues resulting in distorted growth or function[3].

in dogs, three types have been recognised:

Mucopolysaccharides are complex sulphated sugars with repeating disaccharide motifs that form sulphated glycosaminoglycans (GAG). There are five different GAG: chondroitin 4-sulphate, chondroitin 6-sulphate, heparan sulphate, dermatan sulphate and keratan sulphate[12]. In this inherited disease, enzyme deficiency of arylsulfatase leads to accumulation of chondroitin, heparan, and dermatan sulfate glycosaminoglycans in lysosomes of many different cell types, mainly in the connective tissue[13].

Affected dogs are usually young (2- 5 months of age), and although showing normal behavioural activities and appetite, are often unable to walk and function properly and have severe growth retardation. Weakness of the hind legs is evident, followed by a progressive dysfunction of all limbs. Neurological disease is not a feature of this condition.

Other typical features include growth retardation, dwarfism, facial and other skeletal dysmorphisms, and corneal clouding. Joints are extremely lax and easily subluxated and radiographic examination showed severe epiphyseal dysplasia. Skeletal disease appears to be more severe in MPS VII compared with MPS I in dogs[14].

Abnormalities in several other organs are often present including hepatomegaly, tracheal dysplasia, congestive heart failure (due to cardiomegaly, thickening of the heart valves and arterial narrowing due to atherosclerotic ('Hurler') plaques[15]), Wallerian degeneration of the spinal cord, corneal opacities and lymphadenopathy. Ocular lesions are characterized by accumulation of GAG primarily in corneal stromal cells and scleral fibroblasts[16].

Congenital and progressive signs become evident within the first four weeks of life[1].

Deficient β-glucuronidase activity leads to an elevation of GAGs in urine and therefore the quantitative measurement of urinary GAGs can be used in screening patients (toluidine test).

Radiographs usually reveal prominent spondyloepiphyseal dysplasia due to a delayed ossification.

Diagnosis is based on DNA testing and demonstration of reduced arylsulphatase B activity (affected dogs usually around 8.0 - 10.0 pmol/min/mg protein (units); normal 1,049 and 1,968 units). Commercial tests are available for diagnosis of MPS VI in Miniature Pinschers and Miniature Schnauzers.

The primary differential diagnosis for this condition would be glycogen storage disease (caused by glucose-6-phosphatase deficiency).

There is no specific treatment for this condition, although enzyme replacement therapy given shortly after birth using recombinant human alpha-l-iduronidase has shown promise in dog studies[17][18][19].

The prognosis is considered poor and many cases are euthanased due to deteriorating quality of life.

References

  1. 1.0 1.1 Hytönen MK et al (2012) A novel GUSB mutation in Brazilian terriers with severe skeletal abnormalities defines the disease as mucopolysaccharidosis VII. PLoS One 7(7):e40281
  2. Jolly RD et al (2012) Mucopolysaccharidosis type VI in a Miniature Poodle-type dog caused by a deletion in the arylsulphatase B gene. N Z Vet J 60(3):183-188
  3. Neufeld EF & Muenzer J. The Mucopolysaccharidoses (2001) In: Scriver CR, Beaudet AL, Valle D, Sly WS, editors. The Metabolic and Molecular Bases of Inherited Diseases. McGraw-Hill Professional. pp:3421–3452
  4. Shull RM et al (1984) Morphologic and biochemical studies of canine mucopolysaccharidosis I. American Journal of Pathology 114:487–495
  5. Crawley AC et al (2011) Enzyme replacement reduces neuropathology in MPS IIIA dogs. Neurobiol Dis 43(2):422-434
  6. Jolly RD et al (2007) Pathology of mucopolysaccharidosis IIIA in Huntaway dogs. Vet Pathol 44(5):569-578
  7. Neer TM et al (1995) Clinical vignette: mucopolysaccharidosis type VI in a miniature Pinscher. Journal of Veterinary Internal Medicine 9:429–433
  8. Haskins M et al (2008) Clinical Biochemistry of Domestic Animals. Burlington, USA: Elsevier Inc. Lysosomal storage diseases; pp:731–749
  9. Sly WS et al (1973) Beta glucuronidase deficiency: Report of clinical, radiologic, and biochemical features of a new mucopolysaccharidosis. J Pediatr 82(2):249–257
  10. Silverstein Dombrowski DC et al (2004) Mucopolysaccharidosis type VII in a german shepherd dog. J Am Vet Med Assoc 224(4):553–557
  11. Haskins ME et al (1984) Beta-glucuronidase deficiency in a dog: a model of human mucopolysaccharidosis type VII. Pediatric Research 18:980–984
  12. Neufeld EF & Meuezner J (2001) The mucopolysaccharidoses. In: Scriver R, Beaudet AL, Sly WS, Valle D, editors. The Metabolic Bases of Inherited Disease. New York, USA: McGraw-Hill. pp:3421–3452
  13. Smith LJ et al (2012) Effect of neonatal gene therapy on lumbar spine disease in mucopolysaccharidosis VII dogs. Mol Genet Metab 107(1-2):145-152
  14. Herati RS et al (2008) Radiographic evaluation of bones and joints in mucopolysaccharidosis I and VII dogs after neonatal gene therapy. Mol Genet Metab 95(3):142-151
  15. Lyons JA et al (2011) Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. Lab Invest 91(5):665-674
  16. Newkirk KM et al (2011) Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy. Invest Ophthalmol Vis Sci 52(8):5130-5135
  17. Dickson PI et al (2012) Specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis I. Mol Genet Metab 106(1):68-72
  18. Chen A et al (2011) Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase. APMIS 119(8):513-521
  19. Dierenfeld AD et al (2010) Replacing the enzyme alpha-L-iduronidase at birth ameliorates symptoms in the brain and periphery of dogs with mucopolysaccharidosis type I. Sci Transl Med 2(60):60-89
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