Idiopathic Hypocalcemia (IH) / Equine Familial Isolated Hypoparathyroidism (EFIH)

Idiopathic hypocalcemia is a fatal hereditary disease. In 1997, the first case of the disease was described in the Thoroughbred breed. Affected foals suffered from seizures, convulsions, increased sweating, marked stiffness of gait, frequent recumbency, and an inability to stand. These symptoms were caused by a combination of low blood calcium levels, elevated phosphorus levels, and reduced or, given the condition, inappropriately normal parathyroid hormone levels. The parathyroid glands could not be identified during necropsy. The disease develops very soon after birth, usually between 4 and 35 days of age. Due to the severity of the symptoms, affected foals die shortly after the onset of the disease or have to be euthanized.

The disease is caused by a mutation in the RAPGEF5 gene (g.54108297G>T). The mutation occurs at a relatively low frequency in the Thoroughbred population. Nevertheless, genetic testing is important to prevent unintended mating of potential heterozygous carriers of the mutation.

The mutation is inherited in an autosomal recessive manner. The disease therefore develops in individuals that inherit the mutated allele from both parents. These individuals are designated P/P (positive/positive). Carriers of the mutated allele, designated N/P (negative/positive), have inherited the mutation from only one parent and show no clinical signs. However, they can pass the mutation on to their offspring.

When two heterozygous carriers (N/P) are mated, theoretically 25% of the offspring will be clear, 50% will be carriers, and 25% will inherit two copies of the mutation and be affected by IH/EFIH. A mating between a clear individual (N/N) and a carrier (N/P) theoretically produces 50% carriers and 50% clear offspring. If a carrier (N/P) is mated with an affected individual (P/P), theoretically 50% of the offspring will be affected and 50% will be carriers.

.

References:

Elcombe, Megan E., et al. "Prevalence of the RAPGEF5 c. 2624C> A and PLOD1 c. 2032G> A variants associated with equine familial isolated hypoparathyroidism and fragile foal syndrome in the US Thoroughbred population (1988–2019)." Equine Veterinary Journal 55.4 (2023): 666–671.

Rivas, Victor N., et al. "A nonsense variant in Rap Guanine Nucleotide Exchange Factor 5 (RAPGEF5) is associated with equine familial isolated hypoparathyroidism in Thoroughbred foals." PLoS Genetics 16.9 (2020): e1009028.