Overview
of ADH1

What Is ADH1?

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare genetic condition and a major cause of nonsurgical hypoparathyroidism.1

It is an inherited endocrine disorder characterized by2

  • Decreased parathyroid hormone (PTH) secretion
  • Lower serum calcium levels
  • Increased urinary calcium excretion

ADH1 affects up to 1 in 25,000 people

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare genetic condition and a major cause of nonsurgical hypoparathyroidism.1

ADH1 affects up to 1 in 25,000 people

It is an inherited endocrine disorder characterized by2

  • Decreased parathyroid hormone (PTH) secretion
  • Lower serum calcium levels
  • Increased urinary calcium excretion

ADH1 is primarily an inherited condition. A child has a 50% chance
of having ADH1 if they have an affected parent.2

ADH1 Is a Distinct Form of
Hypoparathyroidism

Hypoparathyroidism can result from surgical or nonsurgical etiologies, which include genetic disorders.1 ADH1 is a genetic form of nonsurgical hypoparathyroidism caused by gain-of-function variants in the calcium-sensing receptor gene (CASR), of which over 100 are known. These variants encode the calcium-sensing receptor (CaSR), which increases sensitivity to calcium, reduces PTH secretion and renal calcium reabsorption, and disrupts mineral homeostasis.1,2 The mechanism of disease in ADH1 is distinct from that of other forms of hypoparathyroidism because of the critical role of the CaSR in both the parathyroid glands and the kidneys.2,4

a human body image depicting thyroid and parathyroid glands, CasR and kidneys

What Causes ADH1?

Gain-of-function variants in the CASR gene are the root cause of ADH1. According to a genetic testing program sponsored by BridgeBio, out of 181 samples tested through March 2023, CASR variants accounted for approximately 20% of nonsurgical hypoparathyroidism cases.1,2,5

The CASR gene encodes a protein called the calcium-sensing receptor (CaSR).3,6 CaSR is highly present in the parathyroid glands and kidneys, and it is essential in regulating calcium homeostasis.6-8 CaSR regulates serum Ca2+ levels by adjusting PTH secretion and Ca2+ reabsorption in the kidneys.6 When calcium levels decrease, CaSR signals increase PTH secretion from the parathyroid glands and increase calcium reabsorption in the kidney. This results in increased serum calcium concentrations and decreased urinary calcium concentrations.2

In ADH1, gain-of-function CASR variants cause the CaSR to be overly sensitive to calcium, thereby causing it to detect low blood calcium levels as "normal."2 This leads to decreased PTH secretion from the parathyroid glands and decreased calcium reabsorption in the kidney, resulting in low blood calcium levels (hypocalcemia) and high or inappropriately normal urine calcium levels (hypercalciuria).2

Normal CaSR Function
CaSR with Activating Variant

Due to the critical role of CaSR on the functions of the parathyroid gland
and kidneys, patients with ADH1 often present with both hypocalcemia and
hypercalciuria, along with hypercalciuria-associated complications
(nephrocalcinosis, nephrolithiasis, and renal impairment).2,9

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References

1. Mannstadt M, Cianferotti L, Gafni RI, et al. Hypoparathyroidism: genetics and diagnosis. J Bone Miner Res. 2022;37(12):2615-2629. doi:10.1002/jbmr.4667
2. Roszko KL, Stapleton Smith LM, Sridhar AV, et al. Autosomal dominant hypocalcemia type 1: a systematic review. J Bone Miner Res. 2022;37(10):1926-1935. doi:10.1002/jbmr.4659
3. Dershem R, Gorvin CM, Metpally RPR, 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. doi:10.1016/j.ajhg.2020.04.006
4. Roszko KL, Bi RD, Mannstadt M. Autosomal dominant hypocalcemia (hypoparathyroidism) types 1 and 2. Front Physiol. 2016;18;7:458. doi:10.3389/fphys.2016.00458
5. Mathew AS, Sridhar AV, Roberts MS, Smith LMS, Adler SH, Mannstadt M. Gain-of-function CASR variants, a common genetic cause of non-surgical hypoparathyroidism: findings from a sponsored genetic testing program. Poster presented at: American College of Medical Genetics and Genomics; March 12-16, 2024; Toronto, Canada. Accessed October 11, 2024. https://investor.bridgebio.com/static-files/feaa7b5b-5b43-4b7d-b185-ae56222c9324
6. Fan Y, Liu W, Bi R, et al. Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis a nd parathyroid hyperplasia. Proc Natl Acad Sci U S A. 2018;115(16):E3749-E3758. doi:10.1073/pnas.1717754115
7. Riccardi D, Valenti G. Localization and function of the renal calcium-sensing receptor. Nat Rev Nephrol. 2016;12(7):414-425. doi:10.1038/nrneph.2016.59
8. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol. 2018;15(1):33-51. doi:10.1038/s41574-018-0115-0
9. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med. 1996;335(15):1115-1122. doi:10.1056/NEJM199610103351505