Mucopolysaccharidosis Type VI (Variant 1)

Mucopolysaccharidosis type VI (MPS VI) is an inherited lysosomal storage disorder caused by deficiency of the enzyme N-acetylgalactosamine-4-sulfatase. This deficiency prevents the proper degradation of glycosaminoglycan dermatan sulfate, leading to its accumulation in tissues and organs. Clinical symptoms of MPS VI vary from severe skeletal deformities and growth retardation to milder forms of the disease.

Symptoms

Affected cats show a variety of distinctive clinical symptoms usually beginning between 6 and 8 weeks of age, the severity of which can vary depending on the specific mutation present. These include growth retardation, facial dysmorphia with broad faces, short noses and small ears. In addition, they may present with paresis or paralysis of the hind limbs, as well as generalized osteopenia.

Disease Management

The treatment of MPS VI is based on symptomatic and supportive management strategies, since curative treatment is not yet available. Enzyme replacement therapy and gene therapy with adeno-associated viral vectors (AAV) can be considered, which have shown promising results but are still under development and investigation.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the cat, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected cat must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between cats carrying genetic variants that may cause disease is not recommended, even if they do not show symptoms.

Technical report

Mucopolysaccharidosis type VI is caused by a deficiency of N-acetylgalactosamine-4-sulfatase, a lysosomal enzyme crucial for the degradation of dermatan sulfate glycosaminoglycan. This glycosaminoglycan is a complex polysaccharide composed of long chains of repeating disaccharides. Mucopolysaccharidosis type VI is characterized by lysosomal accumulation and urinary excretion of sulfated glycosaminoglycans. In cats with MPS VI, clinical symptoms can range from severe to relatively mild, depending on the mutation present. The L476P mutation (c.1427T>C) involves a thymine-to-cytosine transition in the ARSB gene, resulting in the substitution of a leucine for a proline, affecting the structure and function of the enzyme N-acetylgalactosamine-4-sulfatase. Another genetic variant has also been identified in this same gene, known as D520N, which in compound heterozygous combination with the L476P variant (one copy of each variant) results in a "mild" MPS VI phenotype. Although this genotype is classified as mild, compound heterozygous cats may develop severe joint disease in old age.

Most affected breeds

Domestic Shorthair
Siamese

Bibliography

Auclair D, Finnie J, Walkley SU, et al. Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats. Pediatr Res. 2012 Jan