Mucopolysaccharidosis In Cats

Mucopolysaccharidosis In Cats

Mucopolysaccharidosis is a group of metabolic disorders characterized by an enzymatic deficiency and improper digestion of glycosaminoglycans (GAGs). There are three types of mucopolysaccharidosis in cats: MPS I, MPS VI and MPS VII. These coincide with human mucopolysaccharidoses types: Hurler syndrome, Maroteaux-Lamy syndrome and Sly syndrome, respectively.

Background information

Mucopolysaccharidosis is a group of metabolic disorders characterized by a deficiency in the production or functioning of lysosomal enzymes required for digestion of glycosaminoglycans (GAGs). GAGs are long unbranched polysaccharides consisting of repeating disaccharide units. Cats suffering from any type of mucopolysaccharidosis either don't produce enough of one of the enzymes involved in the digestion of these polysaccharides or produce enzymes which function improperly. This results in the accumulation of GAGs in cells and tissues and, eventually, progressive cellular damage.

tabby cat sleeping

There are three noted types of mucopolysaccharidosis in cats, each characterized by distinct enzymatic deficiencies and genetic mutations. These are MPS I, MPS VI and MPS VII, coinciding with human cases of Hurler syndrome, Maroteaux-Lamy syndrome and Sly syndrome, respectively. MPS I is determined by a deficiency of the α-1-iduronidase enzyme (IDUA). As a result, cells can't catabolize the glycosaminoglycans heparan and dermatan sulfates which leads to the accumulation of these GAGs within cells (Hinderer et al, 2014 & Gurda et al, 2017). Mucopolysaccharidosis type VI is characterized by a deficiency in the enzyme called arylsulfatase B. This leads to the lysosomal accumulation of dermatan sulfate (Gurda et al, 2017). Mucopolysaccharidosis VII is characterized by a deficiency of the β-glucuronidase enzyme which leads to incomplete degradation of glucoronate-containing GAGs (Fyfe et al, 1999 & Gurda et al, 2017).

Genetics

Mucopolysaccharidosis I

Two mutations in the IDUA gene have been identified as causes for the feline deficiency of the α-1-iduronidase (IDUA) enzyme (Lyons, 2012). The defect variants of this gene are inherited in an autosomal recessive mode, meaning that a cat must inherit two mutated copies of the gene (alleles), one from each parent, in order to be affected by the disorder. Cats who carry only one mutated allele and one healthy allele remain silent carriers (they can pass on the trait to their offspring but aren't affected themselves). If two silent carriers cross, there is a 25% chance that each kitten will be affected. Two affected cats give only affected offspring.

Mucopolysaccharidosis VI

Two point mutations in the ARSB gene have been identified as causes for the feline deficiency of the arylsulfatase B enzyme (Lyons, 2012). The defect variants of this gene are inherited in an autosomal recessive mode, meaning that a cat must inherit two mutated copies of the gene (alleles), one from each parent, in order to be affected by the disorder. Cats who carry only one mutated allele and one healthy allele remain silent carriers (they can pass on the trait to the offspring but aren't affected themselves). If two silent carriers cross, there is a 25% chance for each kitten to be affected. Two affected cats give only affected offspring.

Mucopolysaccharidosis VII

The deficiency of the β-glucuronidase (GUSB) enzyme is caused by a deletion mutation in the GUSB gene, which codes for this enzyme (Fyfe et al, 1999 & Lyons, 2012). The mutation is inherited in an autosomal recessive mode, meaning that a cat must inherit two mutated copies of the gene (alleles), one from each parent, in order to be affected by the disorder. Cats who carry only one mutated allele and one healthy allele remain silent carriers (they can pass on the trait to the offspring but aren't affected themselves). If two silent carriers cross, there is a 25% chance for each kitten to be affected. Two affected cats give only affected offspring.

recessive mode of inheritance in cats Recessive mode of inheritance

Symptoms and diagnosis

Mucopolysaccharidosis V

Due to their inability to catabolize heparan and dermatan sulfates, cats suffering from IDUA deficiency experience various difficulties such as bone and joint deformity, upper airway obstruction, hepatosplenomegaly, cornea clouding and cognitive impairment. Furthermore, the accumulation of GAGs in the coronary arteries and the myocardium can lead to cardiac disease (Hinderer et al, 2014). Clinical presentation also involves urinary GAG excretion and cases with facial dysmorphia were recorded too (Haskins et al, 1983). Diagnosis is usually conducted through clinical examination, urine tests and enzyme assays.

Mucopolysaccharidosis VI and VII

Clinical presentation of the feline MPS VI and VII is similar and involves facial dysmorphia, corneal clouding, hepatomegaly, skeletal deformities, growth retardation, cardiac abnormalities and GAG excretion in urine (Gurda et al, 2017). Diagnosis is usually conducted through clinical examination, urine tests or enzyme assays.

Treatment and prognosis

Research indicates that hematopoietic stem cell transplantation (HSCT) and gene therapy have potential for treatment of feline MPS of all types. The life expectancy of the affected cats depends on the severity of the disease and is generally reduced due to respiratory, neurodegenerative and intestinal abnormalities. Cats with mild cases have a longer life expectancy and can live well into the second decade of life (Gurda et al, 2017). Meanwhile, cats with severe cases have a life expectancy of less than 7 years (Hinderer et al, 2014). Note: It is recommended not to breed carriers in order to prevent the progression of the condition to the offspring. A genetic test is now available for the detection of the mutation, which is now included in the Basepaws health report.

Tabby white-spotted cat with flopped ears

Mucopolysaccharidosis in cats has a relatively poor prognosis. Several treatment options are still being developed, and an affected cat’s life expectancy and quality largely depend on the severity of the disease. The safest measures against mucopolysaccharidosis in cats is in preventing the succession of the genetic mutation through generations.

Bibliography

1. Fyfe JC, Kurzhals RL, Lassaline ME, Henthorn PS, Alur PRK, Wang P, Wolfe JH, Giger U, Haskins ME, Patterson DF, Sun H, Jain S, Yuhki N. (1999) Molecular Basis of Feline b-Glucuronidase Deficiency: An Animal Model of Mucopolysaccharidosis VII. Genomics: 58:121-128

2. Gurda BL, Bradbury AM, Vite CH. (2017). Canine and Feline Models of Human Genetic Diseases and Their Contributions to Advancing Clinical Therapies. Yale Journal of Biology and Medicine. 90(3): 417-431. PMCID: PMC5612185

3. Haskins ME, Jezyk PF, Desnick RJ, McDonough SK, Patterson DF. (1983) The Pathology of the Feline Model of Mucopolysaccharidosis I. American Journal of Pathology. 112(1): 27-36. PMCID: PMC1916323

4. Hinderer C, Bell P, Gurda BL, Qiang W, Louboutin JP, Zhu Y, Bagel J, O'Donnell P, Sikora T, Ruane T, Wang P, Haskins ME, Wilson JM. (2014). Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proceedings of the National Academy of Sciences of the USA. 111(41): 14894–14899. PMCID: PMC4205647

5. Lyons LA (2012). Genetic testing in domestic cats. Molecular and Cellular Probes: 1-7. doi:10.1016/j.mcp.2012.04.004

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