what is autosomal dominant hypocalcemia type 1?

Autosomal dominant hypocalcemia type 1 (ADH1) is a common form of genetic hypoparathyroidism. Gain-of-function variants in the calcium-sensing receptor gene (CASR ) are the root cause of ADH1.¹

BridgeBio is dedicated to improving the lives of people with ADH1 through the development of encaleret, an investigational, orally administered treatment targeting CASR activation. Encaleret is being developed in partnership with BridgeBio affiliate Calcilytix Therapeutics.

Our Research

mother holding son with autosomal dominant hypocalcemia type 1

about ADH1

People with autosomal dominant hypocalcemia type 1 (ADH1) carry a gain-of-function variant in the CASR gene, which encodes the calcium-sensing receptor protein (CaSR).² CASR variants have been found to account for more than 20% of nonsurgical hypoparathyroidism cases, with an estimated 13,000 carriers in the US alone.^3,4 ADH1 is often passed down from parent to child but can occur without a family history of the disease.²

The CaSR constantly monitors and balances blood calcium (Ca²⁺) levels by regulating parathyroid hormone (PTH) secretion and calcium (Ca²⁺) reabsorption in the kidneys.^2,5 In ADH1, the genetic variants cause the CaSR to be more sensitive and responsive to calcium. As a result, low blood calcium levels are detected as “normal” by the CaSR.² This false physiological perception leads to decreased secretion of PTH, low levels of calcium in the blood (hypocalcemia), and high levels of calcium in the urine (hypercalciuria).^2,5

clinical features of ADH1

People with autosomal dominant hypocalcemia type 1 (ADH1) typically experience hypocalcemia, hypercalciuria, and inappropriately low levels of PTH.² Symptoms of hypocalcemia may include severe muscle cramps, muscle spasms (tetany), a burning or prickling sensation in the hands or feet (paresthesia), and seizures.² Hypercalciuria may result in kidney calcification (nephrocalcinosis), kidney stones (nephrolithiasis), and kidney failure.^2,5

Read about our approach

References

Roszko KL, et al. Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2. Front Physiol. 2016;7:458.
Roszko KL, et al. Autosomal Dominant Hypocalcemia Type 1: A Systematic Review. J Bone Miner Res. 2022;37(10):1926 – 1935.
Dershem R, et al. Familial Hypocalciuric Hypercalcemia Type 1 and Autosomal-Dominant Hypocalcemia Type 1: Prevalence in a Large Healthcare Population. Am J Hum Genet. 2020;106(6):734 – 747.
Mannstadt M. Next-Generation Sequencing for Detection of Underlying Genetic Causes of Nonsurgical Hypoparathyroidism: Preliminary Results from a Sponsored Testing Program. Poster presented at Endocrine Society’s Annual Meeting, 2023; Chicago, IL.
Mannstadt M, et al. Hypoparathyroidism: Genetics and Diagnosis. J Bone Miner Res. 2022;37(12):2615 – 2629.