In other species: dog

Categories: Lysosomal storage disease

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 253200 (trait) , 611542 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0009661: mucopolysaccharidosis type 6

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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. Crawley et al. (1998): "L476P homozygotes exhibit dwarfism and facial dysmorphia... . ...D520N/D520N and L476P/D520N cats ... both have normal growth and appearance. In addition, L476P/D520N cats have a high incidence of degenerative joint disease. We conclude that L476P/D520N cats have a very mild MPS VI phenotype not previously described in MPS VI humans."

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). Bravaccini et al. (2022) report clinical signs of a 10-month-old, intact female, Domestic Shorthair cat with mucopolysaccharidosis type VI. Genotyping identified the presence of the ARSB variant L476P. 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."

Breeds: Domestic Shorthair, Siamese (Cat) (VBO_0100221).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: