Vitamin D-Dependent Rickets Type IA

Vitamin D deficiency rickets type IA (RDVD-1A) results from a genetic deficiency of the enzyme 1-hydroxylase, due to mutations in the CYP27B1 gene. This enzyme is crucial for converting calcidiol into the active form of vitamin D, calcitriol, primarily in the kidneys. As a result of this enzyme deficiency, low calcium levels, osteopenia and characteristic bone deformities are observed.

Symptoms

Affected cats usually present with lethargy, difficulty defecating, pelvic limb gait abnormalities and obvious generalized sensitivity to pain. Marked osteopenia and pelvic asymmetry with displacement of the acetabulum towards the midline are also observed. Laboratory values reveal elevated alkaline phosphatase and creatinine kinase levels, and although calcidiol levels are normal, these cats show an inability to effectively convert calcidiol to active calcitriol, essential for intestinal calcium absorption.

Disease Management

Management of this disease focuses on correcting metabolic imbalances and improving the animal`s bone health. The main treatment consists of supplementation of 1,25-dihydroxyvitamin D3 (calcitriol), the active form of vitamin D.

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

Vitamin D deficiency rickets type IA (RDVD-1A) in cats is a metabolic disease characterized by insufficient bone mineralization, resulting in osteomalacia and rickets. This disorder is caused by mutations in the CYP27B1 gene, which codes for the enzyme 1-alpha-hydroxylase. This enzyme is crucial for the conversion of 25-hydroxyvitamin D3 (calcidiol) to the active form of vitamin D, 1,25-dihydroxyvitamin D3 (calcitriol), in the renal tubules. Calcitriol is essential for the regulation of calcium and phosphorus metabolism, facilitating their absorption in the intestine and their deposition in the bones. In cats with RDVD-1A, specific mutations have been identified in the CYP27B1 gene, such as c.637G>T and c.731del, which result in the production of a truncated and nonfunctional protein, severely affecting the enzymatic activity and conversion of calcidiol to calcitriol. In this case, we analyzed the c.637G>T variant described in the Siamese cat. Variations in non-coding regions of the gene have also been observed, but their impact on gene expression is not yet fully understood. Alteration of the last stage of hydroxylation in the kidney is responsible for the low levels of calcitriol in the blood and for the development of the clinical symptoms of the disease.

Most affected breeds

Siamese

Bibliography

Clarke KE, Hurst EA, Mellanby RJ. Vitamin D metabolism and disorders in dogs and cats. J Small Anim Pract. 2021 Nov